TW201925204A - Fused tricyclic compound - Google Patents

Abstract

The present invention addresses the problem of providing a drug to be used to prevent or treat obesity or to prevent or treat type 2 diabetes. The means for solution according to the present invention is a compound represented by general formula (I) or a pharmacologically acceptable salt thereof. [Abbreviated description of each substituent. For example, R1: phenyl group or the like, R2: hydrogen atom or the like, R3: hydrogen atom or the like, R4: hydrogen atom or the like, R5: methyl group or the like, R6: hydrogen atom or the like, R7: heteroaryl group or the like, X: CH2 or the like, Y: CH2 or the like, Z: CH2 or the like].

Description

   Fused tricyclic compound   

The present invention relates to a novel compound having a tricyclic skeleton, which has agonist activity on the GLP-1 receptor, and can be used for the prevention or treatment of obesity, or the prevention or treatment of type 2 diabetes.

Obesity and overweight are defined as abnormal or excessive accumulation of fat in the body at a risk to health. Generally speaking, BMI (Body Mass Index) is used to determine whether it is obese. In the definition of WHO, a BMI value of 25 or more is considered overweight, and 30 or more is considered obese. On the other hand, in Japan, a BMI value of 25 or more is considered obese. Obesity and overweight are considered as risk factors for various diseases such as cardiovascular disease, hypertension, type 2 diabetes, cancer, etc. It is important for public health to eliminate obesity and overweight before suffering from these diseases Problems (Non-Patent Documents 1-2).

Type 2 diabetes is a chronically persistent hyperglycemia due to decreased insulin secretion capacity in pancreatic β cells and / or decreased insulin action in insulin-sensitive organs such as muscle, adipose tissue, and liver. Known in type 2 diabetes, persistent high blood sugar not only causes retinopathy, kidney disease, neuropathy, etc., but also increases the risk of myocardial infarction, cerebral infarction, and the like. As far as prevention of their diseases is concerned, controlling the blood glucose level of patients is considered important. Various drugs are known as drugs for controlling blood glucose levels, for example, insulin preparations, biguanides, SGLT2 inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists, and the like (Non-Patent Document 3) ).

Glucagon-like peptide-1 (GLP-1: Glucagon-Like Peptide-1) is an endogenous peptide secreted mainly from L cells in the lower small intestine in response to eating. GLP-1 binds to the GLP-1 receptor, which is a G protein conjugated receptor, and promotes the production of ATP to cAMP obtained by glucose metabolism for message transmission. The GLP-1 receptor has a glucose concentration-dependent effect on increasing insulin secretion or suppressing appetite, and its agonists have been reviewed for the prevention or treatment of obesity and the prevention or treatment of diabetes (non-patent literature). 4-6). For example, Liraglutide (trade name: Victoza), which is a preparation of human GLP-1 analogues having GLP-1 receptor agonist activity, is an intrinsic factor that causes long-chain fatty acids to easily break down in vivo. GLP-1 is a drug that is acylated and has a longer half-life. It is considered to have a reducing effect on HbA1c that is used as an indicator of blood glucose control in clinical trials for patients with type 2 diabetes. , Europe, and the United States are sold as pharmaceuticals. In addition, liraglutide has been approved as an agent for obesity or overweight patients with obesity or comorbidities associated with obesity in Europe and the United States. However, GLP-1 analogues represented by liraglutide have poor oral absorption due to their active substance being a peptide or a derivative thereof, and most of the analogues have been developed and sold as injections. The injection is poor in the ease of administration and the administration is accompanied by pain, and an oral administration type GLP-1 receptor agonist which can be taken more easily is desired. In addition, the production of GLP-1 analogues such as liraglutide requires a lot of cost compared with the low-molecular-weight pharmaceutical products of the previous type, and it is desirable to have a low-molecular-weight non-peptide GLP- 1 receptor agonist development.

So far, as a non-peptide low-molecular GLP-1 receptor agonist, 1-methyl-4-nitropyrazole derivatives and N- (2-oxoindolin-3-yl) isopropyl Quinoline-3-formamidine derivatives (Patent Literature 1 and Non-Patent Literature 7), oxadiazoanthracene derivatives (Patent Literature 2), and substituted azoanthracene derivatives (Patents Reference 3) and so on. However, their compounds have a different central skeleton from the compounds of the present invention.

Prior art literature Patent literature

Patent Document 1 International Publication No. 2004/103310

Patent Document 2 US Patent Application Publication No. 2009/306063

Patent Document 3 US Patent Application Publication No. 2010/114824

Non-patent literature

Non-Patent Document 1 World Health Organization, Obesity and Overweight [Fact sheet]. (2016) http://www.who.int/media centre / factsheets / fs311 / en /

Non-Patent Document 2 Asia Pac. J. Clin. Nutr. 11, S732-S737, 2002

Non-Patent Document 3 Clin. Cardiol. 2017 Aug 25. doi: 10. 1002 / clc. 22781

Non-Patent Document 4 Lancet 374, 1606-1616 (2009).

Non-Patent Document 5 Int. J. Obes. 38, 689-97 (2014).

Non-Patent Document 6 BMJ 344, d7771 (2012).

Non-Patent Document 7 Acta Pharmacol. Sin. 31, 1026-1030 (2010).

The subject of the present invention is to provide a low-molecular GLP-1 receptor agonist with a novel backbone. In addition, another object of the present invention is to provide a low-molecular-weight GLP-1 receptor agonist having excellent physical properties and excellent effects in mammals (especially humans).

As a result of intensive review in order to solve the above-mentioned problems, the present inventors have created a novel compound having a tricyclic skeleton with agonist activity on the GLP-1 receptor and excellent properties as a pharmaceutical, and have completed it. this invention.

That is, the present invention relates to [1] to [22] described below.

[1] a compound represented by the general formula (I), or a pharmacologically acceptable salt thereof,

[Wherein each substituent is defined as follows: R ¹ : C3-C6 cycloalkyl, phenyl which may be substituted with 1 or 2 halogen atoms, or 6-membered heterocyclic ring which may be substituted with 1 or 2 halogen atoms Aryl

(However, in the case where R ¹ is a phenyl group which may be substituted by 1 or 2 halogen atoms, the phenyl group may form an ortho bond with the terminal of the C1-C6 alkyl group of R ² to form a ring and include R ¹ and R ² (Indane ring or tetralin ring of directly bonded carbon atom)

R ² : hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C3-C5 saturated cyclic ether group

R ³ : hydrogen atom or C1-C6 alkyl

(However, R ² and R ³ can form C3-C5 saturated cyclic ethers which are terminally bonded and contain their directly bonded carbon atoms)

R ⁴ : hydrogen atom or halogen atom

R ⁵ : C1-C6 alkyl, halo C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) methyl, methyl substituted with C3-C5 saturated cyclic ether, di (C1 -C6 alkyl) carbamoylmethyl, 5-membered ring heteroarylcarbonyl which may be substituted by 1 or 2 C1-C6 alkyl groups, 5 or 5 which may be substituted by 1 or 2 C1-C6 alkyl groups 6-membered ring heteroaryl C1-C6 alkyl, or phenyl C1-C6 alkyl which may be substituted by 1 or 2 C1-C6 alkyl groups or may be substituted by 1 or 2 halogen atoms

R ⁶ : hydrogen atom or halogen atom

R ⁷ : 6-membered ring heteroaryl group which may be substituted by 1 or 2 C1-C6 alkyl groups

X: -CH ₂ -,-(C1-C6 alkyl) N-,-((C1-C6 alkyl) carbonyl) N-, or -O-

Y: -CH ₂ -,-(C1-C6 alkyl) N-,-((C1-C6 alkyl) carbonyl) N-, or -O-

Z: -CH _2- , or -O-

(However, when X contains N or O, Y is -CH _2- , and when Y contains N or O, X is -CH _2- )].

[2] The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R ¹ is a phenyl group substituted with one or two halogen atoms, and R ⁴ and R ⁶ are hydrogen atoms.

[3] The compound according to [1] or [2], or a pharmacologically acceptable salt thereof, wherein R ⁷ is pyridyl substituted with one or two C1-C6 alkyl groups.

[4] The compound according to any one of [1] to [3], or a pharmacologically acceptable salt thereof, wherein R ⁵ is a C1-C6 alkyl group, a halogen C1-C6 alkyl group, or a C3-C6 cycloalkane Group, (C3-C6 cycloalkyl) methyl, 6-membered ring heteroaryl C1-C6 alkyl which may be substituted by 1 or 2 C1-C6 alkyl groups, or C1-C6 Alkyl or phenyl C1-C6 alkyl which may be substituted by 1 or 2 halogen atoms.

[5] The compound according to [1], or a pharmacologically acceptable salt thereof, wherein each substituent is selected from the group of substituents: R ¹ : 3,4-dichlorophenyl, 3,5-dichloro Phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, or 4-chloro-3-fluorophenyl

R ² : hydrogen atom, methyl, ethyl, propyl, cyclopropyl, cyclopentyl, cyclohexyl, oxo, tetrahydropiperanyl, or hydroxymethyl

R ³ : hydrogen atom or methyl group

(However, R ² and R ³ may form an oxo ring that is terminally bonded and contains carbon atoms that are directly bonded to them)

R ⁴ : hydrogen atom or fluorine atom

R ⁵ : methyl, ethyl, propyl, isopropyl, isobutyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl Methyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, 1-phenylpropyl, or 2-pyridylmethyl

R ⁶ : hydrogen atom or chlorine atom

R ⁷ : 2,3-dimethyl-4-pyridyl

X: -CH ₂ -,-(CH ₃ ) N-,-(CH ₃ CH ₂ ) N-,-(CH ₃ CO) N-, or -O-

Y: -CH ₂ -,-(CH ₃ ) N-,-(CH ₃ CH ₂ ) N-,-(CH ₃ CO) N-, or -O-

Z: -CH _2- , or -O-

(However, when X contains N or O, Y is -CH _2- , and when Y contains N or O, X is -CH _2- ).

[6] The compound according to [1], or a pharmacologically acceptable salt thereof, which is selected from the group consisting of a compound represented by the following structural formula:

[7] The compound according to [1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[8] The compound according to [1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[9] The compound according to [1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[10] The compound according to [1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[11] The compound according to [1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[12] The compound according to [1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[13] The compound according to [1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[14] A pharmaceutical composition containing the compound according to any one of [1] to [13] or a pharmacologically acceptable salt thereof as an active ingredient.

[15] The pharmaceutical composition according to [14], which is used for preventing or treating obesity.

[16] The use of the compound according to any one of [1] to [13] or a pharmacologically acceptable salt thereof, which is used for producing a pharmaceutical composition for preventing or treating obesity.

[17] A compound according to any one of [1] to [13] or a pharmacologically acceptable salt thereof for use in the prevention or treatment of obesity.

[18] A method for preventing or treating obesity by administering an effective amount of the compound described in any one of [1] to [13] or a pharmacologically acceptable salt thereof.

[19] The pharmaceutical composition according to [14], for preventing or treating type 2 diabetes.

[20] The use of the compound according to any one of [1] to [13] or a pharmacologically acceptable salt thereof, for producing a pharmaceutical composition for preventing or treating type 2 diabetes.

[21] The compound according to any one of [1] to [13] or a pharmacologically acceptable salt thereof for use in the prevention or treatment of type 2 diabetes.

[22] A method for preventing or treating type 2 diabetes by administering an effective amount of the compound described in any one of [1] to [13] or a pharmacologically acceptable salt thereof.

In addition, the present invention is in the following aspects [A-1] to [A-25].

[A-1] a compound represented by the general formula (I), or a pharmacologically acceptable salt thereof,

[Wherein each substituent is defined as follows: R ¹ : C3-C6 cycloalkyl, phenyl which may be substituted with 1 or 2 halogen atoms, or 6-membered heterocyclic ring which may be substituted with 1 or 2 halogen atoms Aryl

(However, in the case where R ¹ is a phenyl group which may be substituted with 1 or 2 halogen atoms, the phenyl group may form an ortho bond with the terminal of the C1-C6 alkyl group of R ² to form a ring and include R ¹ and R hydrindane ² carbon atoms, bonded directly to the ring or a tetrahydronaphthalene ring)

R ² : hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C3-C5 saturated cyclic ether group

R ³ : hydrogen atom or C1-C6 alkyl

(However, R ² and R ³ can form C3-C5 saturated cyclic ethers which are terminally bonded and contain their directly bonded carbon atoms)

R ⁴ : hydrogen atom or halogen atom

R ⁵ : C1-C6 alkyl, halo C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) methyl, methyl substituted with C3-C5 saturated cyclic ether, di (C1 -C6 alkyl) carbamoylmethyl, 5-membered ring heteroarylcarbonyl which may be substituted by 1 or 2 C1-C6 alkyl groups, 5 or 5 which may be substituted by 1 or 2 C1-C6 alkyl groups 6-membered ring heteroaryl C1-C6 alkyl, or phenyl C1-C6 alkyl which may be substituted by 1 or 2 C1-C6 alkyl groups or may be substituted by 1 or 2 halogen atoms

R ⁶ : hydrogen atom or halogen atom

R ⁷ : 6-membered ring heteroaryl group which may be substituted by 1 or 2 C1-C6 alkyl groups

X: -CH ₂ -,-(C1-C6 alkyl) N-,-((C1-C6 alkyl) carbonyl) N-, or -O-

Y: -CH ₂ -,-(C1-C6 alkyl) N-,-((C1-C6 alkyl) carbonyl) N-, or -O-

Z: -CH _2- , or -O-

(However, when X contains N or O, Y is -CH _2- , and when Y contains N or O, X is -CH _2- )].

[A-2] The compound according to [A-1], or a pharmacologically acceptable salt thereof, wherein R ¹ is a phenyl group substituted with one or two halogen atoms, and R ⁴ and R ⁶ are hydrogen atoms.

[A-3] The compound according to [A-1] or [A-2], or a pharmacologically acceptable salt thereof, wherein R ⁷ is pyridyl substituted with 1 or 2 C1-C6 alkyl groups.

[A-4] The compound according to any one of [A-1] to [A-3], or a pharmacologically acceptable salt thereof, wherein R ⁵ is a C1-C6 alkyl group, a halogen C1-C6 alkyl group , C3-C6 cycloalkyl, (C3-C6 cycloalkyl) methyl, 6-membered ring heteroaryl C1-C6 alkyl, which may be substituted with 1 or 2 C1-C6 alkyl, or may be substituted with 1 or 2 C1-C6 alkyl groups or phenyl C1-C6 alkyl groups which may be substituted by 1 or 2 halogen atoms.

[A-5] The compound according to [A-1], or a pharmacologically acceptable salt thereof, wherein each substituent is selected from the following substituent groups: R ¹ : 3,4-dichlorophenyl, 3 , 5-dichlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, or 4-chloro-3-fluorophenyl

R ² : hydrogen atom, methyl, ethyl, propyl, cyclopropyl, cyclopentyl, cyclohexyl, oxo, tetrahydropiperanyl, or hydroxymethyl

R ³ : hydrogen atom or methyl group

(However, R ² and R ³ may form an oxo ring that is terminally bonded and contains carbon atoms that are directly bonded to them)

R ⁴ : hydrogen atom or fluorine atom

R ⁵ : methyl, ethyl, propyl, isopropyl, isobutyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl Methyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, 1-phenylpropyl, or 2-pyridylmethyl

R ⁶ : hydrogen atom or chlorine atom

R ⁷ : 2,3-dimethyl-4-pyridyl

X: -CH ₂ -,-(CH ₃ ) N-,-(CH ₃ CH ₂ ) N-,-(CH ₃ CO) N-, or -O-

Y: -CH ₂ -,-(CH ₃ ) N-,-(CH ₃ CH ₂ ) N-,-(CH ₃ CO) N-, or -O-

Z: -CH _2- , or -O-

(However, when X contains N or O, Y is -CH _2- , and when Y contains N or O, X is -CH _2- ).

[A-6] The compound according to any one of [A-1] to [A-5], or a pharmacologically acceptable salt thereof, wherein X, Y, and Z are selected from one of the following combinations: (1) X:-(C1-C6 alkyl) N-, Y: -CH _2- , Z: -O-; (2) X:-((C1-C6 alkyl) carbonyl) N-, Y: -CH _2- , Z: -O-; (3) X: -CH _2- , Y:-(C1-C6 alkyl) N-, Z: -O-; (4) X: -CH _2- , Y: - ((C1-C6 alkyl) carbonyl) N-, Z: -O -; (5) X: -CH 2 -, Y: -O-, Z: -CH 2 -.

[A-7] The compound according to [A-6], or a pharmacologically acceptable salt thereof, wherein X, Y, and Z are one selected from the group consisting of: (1) X:-(CH ₃ ) N-, Y: -CH _2- , Z: -O-; (2) X:-(CH ₃ CH ₂ ) N-, Y: -CH _2- , Z: -O-; (3) X:- (CH ₃ CO) N-, Y: -CH _2- , Z: -O-; (4) X: -CH _2- , Y:-(CH ₃ ) N-, Z: -O-; (5) X: -CH _2- , Y:-(CH ₃ CH ₂ ) N-, Z: -O-; (6) X: -CH _2- , Y:-(CH ₃ CO) N-, Z: -O -; (7) X: -CH _2- , Y: -O-, Z: -CH _2- .

[A-8] The compound according to [A-6], or a pharmacologically acceptable salt thereof, wherein X, Y, and Z are one selected from the group consisting of: (1) X:-(CH ₃ ) N-, Y: -CH _2- , Z: -O-; (2) X: -CH _2- , Y:-(CH ₃ ) N-, Z: -O-; (3) X: -CH ₂ -, Y: -O-, Z: -CH _2- .

[A-9] The compound according to [A-1], or a pharmacologically acceptable salt thereof, which is selected from the group consisting of a compound represented by the following structural formula:

[A-10] The compound according to [A-1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[A-11] The compound according to [A-1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[A-12] The compound according to [A-1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[A-13] The compound according to [A-1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[A-14] The compound according to [A-1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[A-15] The compound described in [A-1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[A-16] The compound according to [A-1], or a pharmacologically acceptable salt thereof, is represented by the following structural formula:

[A-17] A pharmaceutical composition containing the compound according to any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof as an active ingredient.

[A-18] The pharmaceutical composition according to [A-17], which is used for preventing or treating obesity.

[A-19] Use of a compound according to any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof, which is used for the manufacture of a pharmaceutical composition for preventing or treating obesity Thing.

[A-20] A compound according to any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof for use in the prevention or treatment of obesity.

[A-21] A method for preventing or treating obesity by administering an effective amount of the compound described in any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof.

[A-22] The pharmaceutical composition according to [A-17], which is used for preventing or treating type 2 diabetes.

[A-23] Use of a compound or a pharmacologically acceptable salt thereof as described in any one of [A-1] to [A-16], which is used for the manufacture to prevent or treat type 2 diabetes Pharmaceutical composition.

[A-24] A compound according to any one of [A-1] to [A-16] or a pharmacologically acceptable salt thereof for use in the prevention or treatment of type 2 diabetes.

[A-25] A method for preventing or treating type 2 diabetes by administering an effective amount of a compound as described in any one of [A-1] to [A-16] or a pharmacologically acceptable Of salt.

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is related to the affinity to the GLP-1 receptor, the blood glucose-lowering effect, the weight-loss effect, the food-inhibition effect, and the rate of drug effect expression , Persistence of efficacy, physical stability, solubility, oral absorption, blood concentration, cell membrane permeability, metabolic stability, tissue migration, bioavailability (BA), drug interactions, It has excellent properties such as safety, and is used as a medicine for mammals (especially for humans). Therefore, a pharmaceutical system containing the compound of the present invention as an active ingredient can be used for the purpose of preventing or treating obesity or preventing or treating type 2 diabetes. In addition, the compound of the present invention has 1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline skeleton, 2, 3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline skeleton, and 2,3,4,5,7,8, 9,10-octahydro 呯 幷 [2,3-g] isoquinoline skeleton is difficult to synthesize, so far there is no synthesis example.

Forms used to implement the invention

The present invention will be described in detail below.

In this specification, the terms described below are used.

"C3-C6 cycloalkyl": a 3-6 membered alkyl group, specifically, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

"Halogen atom": a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

"Phenyl which may be substituted by 1 or 2 halogen atoms": a phenyl group, or a phenyl ring whose benzene ring is independently selected (the same applies to the following groups), which is substituted by 1 or 2 halogen atoms, specifically, Phenyl, chlorophenyl (including ortho, meta, and para substituents), fluorophenyl (including ortho, meta, and para substituents), dichlorophenyl (including all substitution patterns), Difluorophenyl (including all substitution patterns), chlorofluorophenyl (including all substitution patterns), and the like.

"6-membered ring heteroaryl": a 6-membered ring aromatic group consisting of a carbon atom and one or more heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Specifically, Pyridyl Base, pyrimidinyl, pyridine Base, or three Base etc.

"6-membered ring heteroaryl which may be substituted with 1 or 2 halogen atoms": an unsubstituted 6-membered ring heteroaryl, or a 6-membered ring hetero with a heteroaryl ring substituted with 1 or 2 halogen atoms Aryl is specifically fluoropyridyl, difluoropyridyl, chloropyridyl, dichloropyridyl, and the like. Dichloropyridyl (including all substitution patterns, but preferably 5,6-dichloro-3-pyridyl), or chloropyridyl (including all substitution patterns, but 5-chloro- is preferred) 3-pyridyl).

"C1-C6 alkyl": a straight or branched chain alkyl group having 1 to 6 carbon atoms, specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Secondary butyl, tertiary butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 3-methylpentyl, 2-methyl Pentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, or 1,2-dimethylbutyl Base etc.

"Hydroxy C1-C6 alkyl": a group substituted with one hydroxy group in the aforementioned C1-C6 alkyl group, specifically, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, Or hydroxyhexyl and the like.

"C1-C6 alkoxy": a group having the aforementioned C1-6 alkyl group bonded to an oxygen atom, and specifically, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy Group, secondary butoxy, tertiary butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, or isohexyloxy and the like.

"C1-C6 alkoxy C1-C6 alkyl group": a C1-C6 alkoxy group substituted with one of the C1-C6 alkyl groups, specifically, methoxymethyl, ethoxy Methyl, propoxymethyl, isopropoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, or isopropoxyethyl.

"C3-C5 saturated cyclic ether group": a monovalent group which is a saturated ring of 4 to 6 member rings and contains one oxygen atom as a constituent atom in the ring, specifically, 2-oxoyl, 3 -Oxofluorenyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropiperanyl, 3-tetrahydropiperanyl, 4-tetrahydropiperanyl, and the like.

"Halo C1-C6 alkyl": a group substituted with 1 to 5 halogen groups in the aforementioned C1-C6 alkyl, specifically, trifluoromethyl, difluoromethyl, 1,1-difluoro Ethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl.

"C3-C6 cycloalkylmethyl": a C3-C6 cycloalkyl group substituted with one methyl group, specifically, cyclopropylmethyl, cyclobutylmethyl, and cyclopentylmethyl , Or cyclohexylmethyl.

"Methyl group substituted with C3-C5 saturated cyclic ether": a methyl group substituted with the aforementioned C3-C5 saturated cyclic ether, specifically, oxygen Methyl, 2-oxomethyl, 3-oxomethyl, 2-tetrahydrofurylmethyl, 3-tetrahydrofurylmethyl, 2-tetrahydropiperanylmethyl, 3-tetrahydropiperanyl Methyl, or 4-tetrahydropiperanylmethyl.

"Di (C1-C6 alkyl) carbamoylmethyl": a group in which a methylamine has two C1-C6 alkyl substituted carbamoyl groups substituted on the N atom, specifically, di Methylaminomethylmethyl, diethylaminomethylmethyl, dipropylaminomethylmethyl, or dibutylaminomethylmethyl, and the like.

"5-membered ring heteroaryl": a 5-membered ring aromatic group composed of a carbon atom and one or more heteroatoms independently selected from the group containing nitrogen, oxygen, and sulfur atoms other than carbon atoms, Specifically, it is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, Oxazolyl, iso Oxazolyl, Diazolyl, thiazolyl, or thiadiazolyl.

"5-membered ring heteroarylcarbonyl group": the aforementioned 5-membered ring heteroaryl group having one carbonyl group is bonded at any position, and specifically, pyrrolylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, furylcarbonyl , Thienylcarbonyl, Oxazolylcarbonyl, or iso Oxazolylcarbonyl and the like.

"5- or 6-membered ring heteroaryl C1-C6 alkyl group": the aforementioned 5-membered ring heteroaryl group or the 6-membered ring heteroaryl group which has 1 in the aforementioned C1-C6 alkyl group, and is based on a substituted group at any position, specifically In other words, pyrazolylmethyl, imidazolylmethyl, furylmethyl, Azolylmethyl, Oxazolyl ethyl, iso Azolylmethyl, or pyridylmethyl, and the like.

"Phenyl C1-C6 alkyl group": a group substituted with a phenyl group in the aforementioned C1-C6 alkyl group, specifically, benzyl, 1-phenylethyl, 2-phenylethyl, 1-benzene Propyl, 2-phenylpropyl, 3-phenylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, or 4-phenylbutyl.

"5-membered ring heteroarylcarbonyl which may be substituted with 1 or 2 C1-C6 alkyl groups": unsubstituted 5-membered ring heteroaryl or heteroaryl ring with 1 or 2 of the aforementioned C1-C6 alkanes The carbonyl group bonded to the aforementioned 5-membered ring heteroaryl group is specifically a pyrazolylcarbonyl group, an imidazolylcarbonyl group, Oxazolylcarbonyl, iso Oxazolylcarbonyl, 1-methylpyrazolylcarbonyl, 1-methylimidazolylcarbonyl, methyliso Oxazolylcarbonyl, methyl Oxazolylcarbonyl, or dimethyl Oxazolylcarbonyl, etc., preferably (2,5-dimethyl Azole 4-yl) carbonyl.

"5 or 6-membered ring heteroaryl C1-C6 alkyl which may be substituted with 1 or 2 C1-C6 alkyl groups": the aforementioned C1-C6 alkyl group or The aforementioned C1-C6 alkyl group substituted with the aforementioned C1-C6 alkyl group substituted with the aforementioned 5- or 6-membered ring heteroaryl group, specifically, is pyrazolylmethyl, imidazolylmethyl, Azolylmethyl, Oxazolyl ethyl, methyl Azolylmethyl, dimethyl Oxazolylmethyl, iso Oxazolylmethyl, methyliso Azolylmethyl, pyridylmethyl, or Methyl, etc., preferably 2-pyridylmethyl, -3-ylmethyl, (5-methyl Azole 3-yl) methyl, (2,5-dimethyl 3-azole) methyl, or (5-methyliso Azole 3-yl) methyl.

"C1-C6 alkyl which may be substituted by 1 or 2 or phenyl C1-C6 alkyl which may be substituted by 1 or 2 halogen atoms": the aforementioned C1-C6 alkyl substituted by phenyl, or One or two of the aforementioned C1-C6 alkyl groups or one or two of the aforementioned halogen atom-substituted phenyl groups, and the aforementioned C1-C6 alkyl group is preferably benzyl, 1-phenylethyl, 2-benzene Ethyl, 1-phenylpropyl, 2-methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, or 3-chlorobenzyl and the like.

"6-membered ring heteroaryl which may be substituted by 1 or 2 C1-C6 alkyl groups": is an unsubstituted 6-membered ring heteroaryl, or the aforementioned C1-C6 heteroaryl ring may be substituted by 1 or 2 C6 alkyl substituted 6-membered ring heteroaryl, specifically, pyridyl, Base, pyrimidinyl, pyridine Base, three Group, methylpyridyl (including all substitution patterns), dimethylpyridyl (including all substitution patterns), and the like.

"(C1-C6 alkyl) carbonyl": a group in which one of the aforementioned C1-C6 alkyl groups is bonded to a carbonyl group, and specifically, ethenyl, propionyl, butylmethyl, isobutylmethyl, or trimethyl Acetyl and the like are preferably ethenyl or propionyl.

The substituents R ¹ to R ⁷ used in the general formula (I) in the present invention will be described below.

The preferred substituent R ¹ in the present invention is a phenyl group which may be substituted with 1 or 2 halogen atoms, further preferably a phenyl group which is substituted with 1 or 2 halogen atoms, and more preferably 2 halogen groups. Atom-substituted phenyl, more preferably 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro- 4-fluorophenyl, or 4-chloro-3-fluorophenyl. Particularly preferred is 3,4-dichlorophenyl.

The preferred substituent R ² in the present invention is a hydrogen atom, a methyl group, an ethyl group, a propyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, an oxofluorenyl group, a tetrahydropiperanyl group, or a hydroxymethyl group, more It is preferably a hydrogen atom, a methyl group, or an ethyl group.

In one aspect of the present invention, the substituents R ¹ and R ² may form an indane ring or a tetrahydronaphthalene ring that is bonded at the ends and includes a carbon atom directly bonded to R ¹ and R ² .

The preferred substituent R ³ in the present invention is a hydrogen atom or a C1-C6 alkyl group, more preferably a hydrogen atom, a methyl group, or an ethyl group, and still more preferably a hydrogen atom or a methyl group.

As one aspect of the present invention, the substituents R ² and R ³ may form a C3-C5 saturated cyclic ether (preferably an oxo ring) which is bonded to the terminal and contains a carbon atom directly bonded to R ² and R ³ . .

The preferred substituent R ⁴ in the present invention is a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, and still more preferably a hydrogen atom.

Preferred substituents R ⁵ in the present invention are methyl, ethyl, propyl, isopropyl, isobutyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl , Cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, 1-phenylpropyl, or 2-pyridylmethyl, more preferably isobutyl, cyclopentyl, cyclo Hexyl, cyclobutylmethyl, or cyclopentylmethyl.

The preferred substituent R ⁶ in the present invention is a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a chlorine atom, and still more preferably a hydrogen atom.

The preferred substituent R ⁷ in the present invention is a 6-membered ring heteroaryl group which may be substituted with 1 or 2 C1-C6 alkyl groups, more preferably a pyridyl group substituted with 1 or 2 C1-C6 alkyl groups. And more preferably 2,3-dimethyl-4-pyridyl.

Examples of the selected substituent of X or Y in the present invention include a methylene group (-CH _2- ), a nitrogen atom substituted with a C1-C6 alkyl group (-(C1-C6 alkyl) N- ), A nitrogen atom (-((C1-C6 alkyl) carbonyl) N-), and an oxygen atom (-O-) substituted with a (C1-C6 alkyl) carbonyl group, but the following substituents are preferred.

X: -CH ₂ -,-(CH ₃ ) N-,-(CH ₃ CH ₂ ) N-,-(CH ₃ CO) N-, or -O-, Y: -CH ₂ -,-(CH ₃ ) N-,-(CH ₃ CH ₂ ) N-,-(CH ₃ CO) N-, or -O-.

However, in the combination of X and Y, oxygen atom and oxygen atom (OO), nitrogen atom and oxygen atom (NO), or nitrogen atom and nitrogen atom (NN), etc. The combination is not included in the present invention.

Preferable Z in the present invention includes a methylene group (-CH _2- ) or an oxygen atom (-O-).

The combination of X, Y, and Z in the present invention is preferably the following combination.

(1) X:-(C1-C6 alkyl) N-, Y: -CH _2- , Z: -O-; (2) X:-((C1-C6 alkyl) carbonyl) N-, Y: -CH _2- , Z: -O-; (3) X: -CH _2- , Y:-(C1-C6 alkyl) N-, Z: -O-; (4) X: -CH _2- , Y:-((C1-C6 alkyl) carbonyl) N-, Z: -O-; (5) X: -CH _2- , Y: -O-, Z: -CH _2-

More preferably, it is the following combination.

(1) X:-(CH ₃ ) N-, Y: -CH _2- , Z: -O-; (2) X:-(CH ₃ CH ₂ ) N-, Y: -CH _2- , Z: -O-; (3) X:-(CH ₃ CO) N-, Y: -CH _2- , Z: -O-; (4) X: -CH _2- , Y:-(CH ₃ ) N- , Z: -O-; (5) X: -CH _2- , Y:-(CH ₃ CH ₂ ) N-, Z: -O-; (6) X: -CH _2- , Y:-(CH ₃ CO) N-, Z: -O-; (7) X: -CH _2- , Y: -O-, Z: -CH _2-

Particularly preferred is the following combination.

(1) X:-(CH ₃ ) N-, Y: -CH _2- , Z: -O-; (2) X: -CH _2- , Y:-(CH ₃ ) N-, Z: -O -; (3) X: -CH _2- , Y: -O-, Z: -CH _2-

The respective structures are shown below in order.

The compound represented by the general formula (I) is preferably the following compounds.

N-[(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- ( 2,3-dimethylpyridin-4-yl) -L-phenylalanine

N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- (2-methyl Propyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine

N-[(4R, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl- 1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] -4- (2,3- (Dimethylpyridin-4-yl) -L-phenylalanine

N-[(2S, 8S) -9-cyclohexyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-2 , 3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-di (Methylpyridin-4-yl) -L-phenylalanine

N-[(4R, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-form -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- (2, 3-dimethylpyridin-4-yl) -L-phenylalanine

N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

N-[(4S, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (Pharmacologically acceptable salt)    

"The pharmacologically acceptable salt" means a salt that can be used as medicine. When a compound has an acidic group or a basic group, it can be made into a "salt with a base" or "acid addition salt" by reacting with a base or an acid. Therefore, this salt is indicated. Moreover, "its pharmacologically acceptable salt" also includes its hydrate.

As far as the pharmacologically acceptable "salts with bases" of the compound are concerned, alkali metal salts such as sodium, potassium, and lithium salts are preferred; alkaline earth metal salts such as magnesium and calcium salts; such as N-formaldehyde base Phosphonium salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinium pyridine salt, formazan Organic base salts of pyridine salts; or amino salts such as glycine, lysine, arginate, ornithine, glutamate, aspartate, preferably alkali Metal salt or alkaline earth metal salt.

As far as pharmacologically acceptable "acid addition salts" of the compound are concerned, preferred are halogenated hydrochlorides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodate; such as nitrate, Inorganic acid salts of perchlorate, sulfate, phosphate, etc .; such as lower alkane sulfonates of mesylate, triflate, ethane sulfonate; such as benzene sulfonate, p-toluene Aryl sulfonates of sulfonates; such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc. Organic acid salts; and amino acid salts such as glycine, lysine, spermine, ornithine, glutamate, aspartate, most preferably halogenated hydrochloride (Especially the hydrochloride).

    (Hydrate, etc.)    

The compound of the present invention or a pharmacologically acceptable salt thereof may be placed in the atmosphere or absorbed by recrystallization, and may adhere to and absorb water to become a hydrate. The present invention also includes such various hydrates, solvates, and Crystal polymorphic compound.

    (Isomers)    

The compounds of the present invention may have tautomers and geometric isomers depending on the type of the substituent. In this specification, although the compound of the present invention may only describe one form of the isomer, the present invention also includes other isomers, and also includes isolated isomers or mixtures thereof.

The compound of the present invention may have an asymmetric carbon atom or an asymmetric axis, and optical isomers based thereon may exist. The present invention also includes isolated optical isomers, or mixtures thereof.

    (Isotopes)    

The compounds of the present invention also include identifiers, that is, compounds in which one or two or more atoms of the compound are substituted with isotopes (for example, ² H, ³ H, ¹³ C, ¹⁴ C, ³⁵ S, etc.).

    (Prodrug)    

The invention also includes pharmacologically acceptable prodrugs of the compounds of the invention. A pharmacologically acceptable prodrug refers to a compound having a group capable of being converted into an amine group, a hydroxyl group, a carboxyl group, or the like under conditions of decomposition by a solvent or physiological conditions. Examples of the base that forms a prodrug include the bases described in Prog. Med., 5, 2157-2161 (1985).

As the prodrug, more specifically, in the case where the compound has an amine group, a compound in which the amine group is fluorinated and phosphorylated (for example, the amine group is eicosanyl group, propylamine group Carbonylation, pentylaminocarbonylation, (5-methyl-2- pendantoxy-1,3-dioxolene-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidinylmethyl Methylated, trimethylacetoxymethylated compounds, etc.) In the case where a hydroxyl group is present in the compound, examples of the hydroxyl group are methylated, alkylated, phosphorylated, borated (for example, The hydroxyl group is acetylated, palmitized, propylated, trimethyl acetylated, succinated, transbutylene difluorinated, propylaminedified, dimethylaminomethylated Carbonylated compounds, etc.) and the like.

In the case where a compound has a carboxyl group, compounds in which the carboxyl group is esterified or amidated (for example, the carboxyl group is ethylated, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl) Esterification, trimethylacetamidooxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidine or methylamidine compounds, etc.).

    (Production method)    

The compound of the present invention and its pharmacologically acceptable salt can be produced by applying various known synthetic methods based on the characteristics of the basic structure or the type of the substituent. At this time, depending on the type of the functional group, from the raw material to the intermediate, protecting the functional group with an appropriate protecting group may be effective in manufacturing technology. Examples of such a protecting group include the protecting groups described by Wuts (PGMWuts) and Greene (TWGreene), Greene's Protective Groups in Organic Synthesis (5th edition, 2014), and the like, depending on the reaction conditions It can be appropriately selected and used, and a person with ordinary knowledge in the technical field can appropriately select the most suitable protecting group.

In this method, after the protective group is introduced and reacted, the protective group is removed as necessary to obtain a desired compound. In addition, the prodrugs of the compound of the present invention can be produced in the same manner as the protective group described above, by introducing a specific group from the raw material to the intermediate, or by further reacting with the obtained compound. The reaction can be carried out by applying a method such as ordinary esterification, amidation, and dehydration.

Each compound of the following A to W methods may be a salt of the compound. Examples thereof include a hydrochloride or a sulfate, or a sodium or potassium salt.

The solvent used for the reaction in each step of the A to W method described below is not particularly limited as long as it does not inhibit the reaction and partially dissolves the starting materials. For example, it is selected from the following solvent groups. The solvent group contains aliphatic hydrocarbons such as hexane, pentane, petroleum ether, and cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethyl Halogenated hydrocarbons of alkane, chlorobenzene, dichlorobenzene; such as diethyl ether, diisopropyl ether, tetrahydrofuran, Ethers of alkane, dimethoxyethane, diethylene glycol dimethyl ether; such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone; such as ethyl acetate, acetic acid Ester of propyl ester, butyl acetate; such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; nitriles such as acetic acid, propionic acid; such as methanol, ethanol, 1-propanol, 2-propanol, Alcohols of 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol; such as formamidine, N, N-dimethylformamide, N , N-dimethylacetamidamine, N-methyl-2-pyrrolidone, phosphoryl hexamethyltriamide, 1,3-dimethyl-3,4,5,6-tetram Hydroxylamines of hydrogen-2H (1H) -pyrimidone (DMPU); such as dimethylarsine, cyclobutyridine, water; and mixtures thereof.

The acid used for the reaction in each step of the following A to W methods is not particularly limited as long as it does not inhibit the reaction, and is selected from the following acid groups. The acid group contains inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid; organic acids such as acetic acid, propionic acid, trifluoroacetic acid, and pentafluoropropionic acid; such as methanesulfonic acid, trifluoromethyl Organic sulfonic acids of sulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid.

The base used for the reaction in each step of the following A to W methods is not particularly limited as long as it does not inhibit the reaction, and is selected from the following base groups. Alkali groups include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium bicarbonate, and potassium bicarbonate; such as lithium hydroxide, sodium hydroxide, and hydrogen Alkali metal hydroxides of potassium oxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; such as lithium amide, sodium amine (sodium amide), potassium amine (potassium amide) alkali metal amines; such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, alkali metal alkoxides; such as lithium diisopropyl Lithium alkylsulfonium amines; such as lithium bistrimethylsilylamine, silylamine of sodium bistrimethylsilylamine; such as n-butyllithium, secondary butyllithium, tertiary Alkyllithium of butyl lithium; such as methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, ethyl magnesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride, isopropyl bromide Alkyl magnesium, isobutyl magnesium chloride, halogenated alkyl magnesium; and triethylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, N-methyl Porphyrin, N-ethyl Fluoroline, pyridine, methylpyridine, 4-dimethylaminopyridine, 4-pyrrolidinium pyridine, 2,6-di-tertiarybutyl-4-methylpyridine, quinoline, N, N-dimethyl Aniline, N, N-diethylaniline, 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), 1,4-diazabicyclo [2,2,2] Organic amines of octane (DABCO), 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU).

In the reactions of the respective steps of the following A to W methods, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.

In the reaction of each step of the following A to W methods, after the reaction is completed, the target compound of each step is isolated from the reaction mixture according to a usual method. The target compound can be obtained by, for example, (i) filtering off insoluble matters such as catalysts as necessary, and (ii) adding water and a water-immiscible solvent (e.g., dichloromethane, acetic acid, etc.) to the reaction mixture. Ethyl ester, etc.) to extract the target compound, (iii) washing the organic layer with water, drying using a desiccant such as anhydrous magnesium sulfate, and (iv) distilling off the solvent. The obtained target compound can be further purified by an ordinary method (for example, recrystallization, reprecipitation, or silica gel column chromatography) according to necessity. The target compound in each step can be used in the next reaction without purification.

In the following steps A to W, each of the optically active amines such as (R) or (S) -phenethylamine can be recrystallized separately or separated by using an optically active column, as desired. To separate and purify optical isomers.

The methods for producing the compounds A to W are described below. However, the manufacturing method is not limited to any of the following methods. In some cases, the abbreviations shown below are used.

Bn: benzyl

Boc: tertiary butoxycarbonyl

Ns: 2-nitrobenzenesulfonyl

p-Ns: 4-nitrobenzenesulfonyl

PG: Protective group

TBDMS: tertiary butyldimethylsilyl

TBDPS: tertiary butyl diphenyl silicon

TIPS: Triisopropyl Silicon

Tf: trifluoromethanesulfonyl

    [Method A]    

Method A is a method for producing the compound (A-V) of the present invention.

[Wherein R ¹ to R ⁷ , X, Y, and Z represent the same meaning as above]

    (Step A1) Hydrolysis reaction    

The step of obtaining the compound (A-II) by partially hydrolyzing the ester of the compound (A-I) by adding 1 equivalent or an excessive amount of an alkaline aqueous solution.

Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, and potassium hydroxide.

The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include water, methanol, ethanol, tetrahydrofuran, dimethoxyethane, acetonitrile, and mixtures thereof. The reaction temperature is usually about 0 to 60 ° C, and the reaction time is usually 0.5 to 24 hours.

This step can be performed by appropriately selecting the reaction conditions described in Wuts (P.G.M.Wuts) and Greene (T.W.Greene) and Greene's Protective Groups in Organic Synthesis (5th edition, 2014).

    (Step A2) Amidation reaction         (When using a condensing agent)    

A step of obtaining a compound (A-IV) by amidating the compound (A-II) with 1 equivalent or an excessive amount of a desired amine (A-III) and a condensing agent.

Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), and 1,1'- Carbonyldiimidazole (CDI), O- (7-azabenzimidazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (HATU), 4-chloride (4,6-dimethoxy-1,3,5-tri -2-yl) -4-methyl Porphyrinium (DMTMM) and the like. In addition, it is sometimes preferable to use an additive for the reaction. Examples of the additives include N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), and the like. In this reaction, in order to make the reaction proceed smoothly, an organic base such as triethylamine, diisopropylethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide is advantageous. situation.

The solvent is not particularly limited as long as it is inert to the reaction, but examples include N, N-dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, Chloroform, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, or a mixture thereof. The reaction temperature is usually from room temperature to 120 ° C, and the reaction time is usually from 0.5 to 24 hours.

    (When using a reactive derivative)    

A step of obtaining a compound (A-IV) by converting the compound (A-II) into a reactive derivative and then reacting it with a desired amine (A-III). Examples of the reactive derivative include acid halides obtained by reacting with halogenating agents such as scopolamine and thionyl chloride, mixed acid anhydrides obtained by reaction with isobutyl chloroformate, and 1-hydroxybenzo. An active ester obtained by condensing a triazole or the like. In this reaction, organic bases such as triethylamine, diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide are advantageous in making the reaction proceed smoothly. .

The solvent may be any solvent that is inert to the reaction, and examples thereof include halogenated hydrocarbons, aromatic hydrocarbons, and ethers. The reaction temperature is usually -20 to 60 ° C, and the reaction time is usually 0.5 to 24 hours.

    (Step A3) Hydrolysis reaction    

The step of obtaining the compound (A-V) of the present invention by adding an alkaline aqueous solution in an equal amount or an excess amount to the solvent and reacting the compound (A-IV) for 0.5 to 24 hours under cooling or heating. This step can be performed in the same manner as step A1.

    [Method B]    

Method B is a method for producing compound (B-VI) (a compound corresponding to compound (A-I) of method A).

[R ¹ to R ^{5 have} the same meanings as above, and R represents C1-C6 alkyl or C1-C6 alkylcarbonyl]

    (Step B1) Deprotection    

This step uses trimethyl iodide or 4N hydrochloric acid / 1,4-di A step of obtaining a compound (B-II) by removing a Boc group from the compound (BI) with an alkane solution. Examples of the reaction solvent include dichloromethane, chloroform, acetonitrile, and mixtures thereof. The reaction temperature is usually 0 to 40 ° C, and the reaction time is usually 0.5 to 12 hours. In addition to these conditions, this step can be performed by appropriately selecting the reaction conditions described in Wuts (PGMWuts) and Greene (TW Greene) and Greene's Protective Groups in Organic Synthesis (5th edition, 2014).

    (Step B2) Deprotection    

This step is a step of obtaining a compound (B-III) by removing a benzyl group from a compound (B-II) using a metal catalyst under a hydrogen environment. Examples of the metal catalyst include palladium catalysts such as palladium carbon, palladium black, and palladium hydroxide; platinum catalysts such as platinum plate and platinum oxide; nickel catalysts such as reduced nickel and Raney nickel; etc. (Rhodium catalysts such as tris (triphenylphosphine) chlororhodium); iron catalysts such as reduced iron, etc. As the reaction solvent, alcohols such as methanol, ethanol, and 2-propanol; Ethyl ether, tetrahydrofuran, di Ethers such as alkane, dimethoxyethane, etc .; water, ethyl acetate, N, N-dimethylformamide, dimethylsulfinium, or a mixture thereof. Instead of hydrogen, formic acid or ammonium formate in an amount of 1 equivalent to an excess relative to compound (B-II) may be used as a hydrogen source. The reaction temperature is usually about 20 to 150 ° C, and the reaction time is about 1 hour to 5 days. In addition to these conditions, this step can be performed by appropriately selecting the reaction conditions described in Wuts (PGMWuts) and Greene (TW Greene) and Greene's Protective Groups in Organic Synthesis (5th edition, 2014).

    (Step B3) Introduction of a substituent to a nitrogen atom    

This step is a step of obtaining compound (B-IV) from compound (B-III) using the following method.

    (When using a reduced amination reaction)    

This step is a step of obtaining a compound (B-IV) from the compound (B-III) using a corresponding aldehyde and a reducing agent.

As the reducing agent, sodium cyanoborohydride, sodium triacetoxyborohydride, 2-methylpyridineborane, and the like can be used. In addition, adding a small amount of an acid such as acetic acid, trifluoroacetic acid, or hydrochloric acid to the reaction system may result in better results.

The solvent is not particularly limited as long as it is inert to the reaction, but examples thereof include alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran, and dihydrogen. Ethers such as alkane, dimethoxyethane, halogen solvents such as dichloromethane, dichloroethane, etc., or mixtures thereof.

The reaction temperature is about 0 to 50 ° C, and the reaction time is usually 0.1 hour to about 3 days.

    (When using amidation reaction)    

This step is a step of obtaining a compound (B-IV) from a compound (B-III) using a sulfonation reaction. This step can be performed in the same manner as step A2.

    (Step B4) O-alkylation    

This step is a step of obtaining a compound (B-VI) by subjecting the compound (B-IV) to O-alkylation.

And a step of obtaining the compound (B-VI) from the compound (B-IV) by using an alcohol in the presence of phosphine and azodicarboxylate, azodimethanamine, or cyanomethylenetrialkylphosphine .

Examples of the phosphine include triphenylphosphine and tri-n-butylphosphine.

Examples of the azodicarboxylate, azodimethanamine, or cyanomethylenetrialkylphosphine include diethyl azodicarboxylate, di-tertiary butyl azodicarboxylate, and 1,1 ' -Azobis (N, N-dimethylformamidine), 1,1 '-(azodicarbonyl) dipiperidine, cyanomethylenetributylphosphine, or cyanomethylenetrimethyl Phosphine, etc.

The reaction solvent is not particularly limited as long as it is inert to the present reaction, and examples thereof include tetrahydrofuran, 1,4-bis Alkane, toluene, or a mixture thereof. The reaction temperature is usually about 0 to 100 ° C, and the reaction time is usually about 0.5 to 24 hours.

    [Method C]    

The method C is a method for producing a compound (C-V) (a compound (B-I) of a method B).

[In the formula, R ⁴ has the same meaning as above, and R represents C1-C6 alkyl or C1-C6 alkylcarbonyl]

    (Step C1) Deprotection    

This step is a step of obtaining the compound (C-II) by removing the TBDMS group from the compound (C-I) using tetrabutylammonium fluoride. When acetic acid is added, good results may be obtained. The reaction solvent is not particularly limited as long as it is inert to the present reaction, and examples thereof include tetrahydrofuran. The reaction temperature is usually 0 to 70 ° C, and the reaction time is usually about 1 hour to 5 days. In addition to these conditions, this step can be performed by appropriately selecting the reaction conditions described in Wuts (P.G.M.Wuts) and Greene (T.W.Greene) and Greene's Protective Groups in Organic Synthesis (5th edition, 2014).

    (Step C2) Cyclization reaction (light extension reaction)    

This step is a step of obtaining a compound (C-III) from a compound (C-II) using a phosphine and an azodicarbonate or azodimethanamine.

Examples of the phosphine include triphenylphosphine and tri-n-butylphosphine.

Examples of the azodicarboxylate or azodimethanamine include diethyl azodicarboxylate, di-tertiary butyl azodicarboxylate, and 1,1'-azobis (N, N-di Methylformamide), or 1,1 '-(azodicarbonyl) dipiperidine.

The reaction solvent is not particularly limited as long as it is inert to the present reaction, and examples thereof include tetrahydrofuran, 1,4-bis Alkane, toluene, or a mixture thereof. The reaction temperature is usually about 0 to 100 ° C, and the reaction time is usually about 0.5 to 24 hours.

    (Step C3) Deprotection    

This step is a step of obtaining a compound (C-IV) by removing a 4-nitrobenzenesulfonyl group from the compound (C-III) using a base and 4-mercaptobenzoic acid.

Examples of the base include potassium carbonate, sodium carbonate, lithium hydroxide, and sodium hydroxide.

The reaction solvent is not particularly limited as long as it is inert to the present reaction, but examples include methylene chloride, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, and dimethyl The reaction temperature is about 0 ~ 60 ° C, and the reaction time is about 1 hour to 3 days. In addition to these conditions, this step can be performed by appropriately selecting the reaction conditions described in Wuts (P.G.M.Wuts) and Greene (T.W.Greene) and Greene's Protective Groups in Organic Synthesis (5th edition, 2014).

    (Step C4) Introduction of a substituent on a nitrogen atom    

This step is a step of obtaining a compound (C-V) by introducing a substituent on a nitrogen atom of the compound (C-IV). This step can be performed in the same manner as step B3.

    [Method D]    

The D method is a method for producing the compound (D-III) (the compound (C-I) of the C method).

[Wherein R ⁴ represents the same meaning as above]

    (Step D1) N-alkylation reaction    

This step is a step of obtaining (D-II) from compound (D-I) by using 1- [4- (benzyloxy) phenyl] -2-propen-1-one or a derivative thereof in the presence of a base.

As the base, triethylamine, diisopropylethylamine, or the like is used. As a reaction solvent, ethanol or the like is used. The reaction temperature is usually 20 to 70 ° C, and the reaction time is usually 1 hour to 3 days.

    (Step D2) Asymmetric reduction    

This step is a step of obtaining a compound (D-III) from a compound (D-II) using an asymmetric reducing agent.

Examples of the asymmetric reducing agent include (S) or (R) -5,5-diphenyl-2-methyl-3,4-propanol-1,3,2-oxazaborolidine Corey-Bakshi-Shibata reducing agent prepared by optically active oxaboridine and borane. The asymmetric reducing agent can be appropriately selected by those having ordinary skill in the art in accordance with the stereochemistry of the desired compound. These modification methods can also be used in this step if necessary. The asymmetric reducing agent in this step is preferably from (R) -5,5-diphenyl-2-methyl-3,4-propanol-1,3,2-oxaboridine and borane Dimethyl sulfide.

The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include tetrahydrofuran, toluene, dichloromethane, and mixtures thereof. The reaction temperature is usually -78 to 60 ° C, and the reaction time is about 0.5 to 24 hours.

    [D ’method]    

The D 'method is a method for producing the compound (D'-VI) (the compound (B-I) of the B method).

[In the formula, R ⁴ has the same meaning as above, and R represents C1-C6 alkyl or C1-C6 alkylcarbonyl]

    (Step D'1) N-alkylation reaction    

This step is based on the use of 1- [4- (benzyloxy) phenyl] -2-propen-1-one or its derivative to obtain compound (D'-I) from compound (D'-I). II). This step can be performed in the same manner as step D1.

    (Step D'2) Introduction of a substituent on a nitrogen atom    

This step is a step of introducing a substituent on a nitrogen atom and obtaining a compound (D'-III) from the compound (D'-II). This step can be performed in the same manner as step B3.

    (D'3 step) Asymmetric reduction    

This step is a step of obtaining a compound (D'-IV) from a compound (D'-III) using an asymmetric reducing agent. This step can be performed in the same manner as step D2.

    (D'4 step) Deprotection    

This step is a step of obtaining a compound (D'-V) by removing a protecting group from the compound (D'-IV). This step can be performed in the same manner as the C1 step.

    (D'5 step) Cyclization reaction    

This step is a step of obtaining a compound (D'-VI) from a compound (D'-V) by using a phosphine and an azodicarboxylate or azodimethylamidine. This step can be performed in the same manner as the step C2.

    [Method E]    

The E method is a method for producing a compound (E-VI) (a mixture of stereoisomers of a compound corresponding to the compound (A-I) of the A method).

[R ¹ to R ^{5 have} the same meanings as above, and R represents C1-C6 alkyl or C1-C6 alkylcarbonyl]

    (Step E1) Deprotection    

This step is a step of obtaining a compound (E-II) by removing a Boc group from the compound (E-I). This step can be performed in the same manner as in step B1.

    (Step E2) Introduction of substituent of nitrogen atom    

This step is a step of obtaining a compound (E-III) by introducing a substituent on a nitrogen atom from the compound (E-II). This step can be performed in the same manner as in the above step B3.

    (Step E3) Deprotection    

This step is a step of obtaining the compound (E-IV) from the compound (E-III) using a palladium catalyst and a nucleophile. Examples of the palladium catalyst include (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphine) ferrocene] dichloropalladium, ginsyl (dibenzylideneacetone) dipalladium, and palladium acetate. , Acetoacetone palladium, or bis (triphenylphosphine) palladium dichloride. Examples of nucleophiles include Phthaloline, 5,5-dimethyl-1,3-dimedone, diethyl malonate, 1,4-diazabicyclo [2.2.2] octane (DABCO), or phenyl Silane, etc. The reaction solvent is not particularly limited as long as it is inert to the present reaction, and examples thereof include tetrahydrofuran, N, N-dimethylformamide, dichloromethane, or a mixture thereof. The reaction temperature is usually about 20 to 100 ° C, and the reaction time is about 0.5 to 24 hours. In addition, this step can be performed by appropriately selecting the reaction conditions described in Wuts (PGMWuts) and Greene (TW Greene) and Greene's Protective Groups in Organic Synthesis (5th edition, 2014).

    (E4 step) O-alkylation    

This step is a step of obtaining compound (E-VI) by performing O-alkylation from compound (E-IV). This step can be performed in the same manner as step B4.

    [F law]    

The F method is a method for producing the compound (F-V) (the compound (E-I) of the E method).

[In the formula, R ⁴ has the same meaning as above, and R represents C1-C6 alkyl or C1-C6 alkylcarbonyl]

    (Step F1) Deprotection    

This step is a step of obtaining a compound (F-II) by removing a protective group from the compound (F-I). This step can be performed in the same manner as the C1 step.

    (Step F2) Cyclization reaction    

This step is a step of obtaining a compound (F-III) from a compound (F-II) using (cyanomethylene) trialkylphosphine, or a phosphine and an azodicarboxylate or azodimethylformamide .

Examples of the (cyanomethylene) trialkylphosphine include (cyanomethylene) trimethylphosphine, cyanomethylene) tributylphosphine, and the like.

Examples of the phosphine include triphenylphosphine and tri-n-butylphosphine.

Examples of the azodicarboxylate or azodimethanamine include diethyl azodicarboxylate, di-tertiary butyl azodicarboxylate, and 1,1'-azobis (N, N-di Methylformamide), or 1,1 '-(azodicarbonyl) dipiperidine.

The reaction solvent is not particularly limited as long as it is inert to the present reaction, and examples thereof include tetrahydrofuran, 1,4-bis Alkane, toluene, or a mixture thereof. The reaction temperature is usually about 0 to 100 ° C, and the reaction time is usually about 0.5 to 24 hours.

    (Step F3) Deprotection    

This step is a step of removing the 4-nitrobenzenesulfonyl group from the compound (F-III) to obtain the compound (F-IV). This step can be performed in the same manner as the step C3.

    (Step F4) Introduction of a substituent on a nitrogen atom    

This step is a step of obtaining a compound (F-V) by introducing a substituent on a nitrogen atom from the compound (F-IV).

This step can be performed in the same manner as in the above step B3.

    [G law]    

The G method is a method for producing the compound (G-V) (the compound (F-I) of the F method).

[Wherein R ⁴ represents the same meaning as above]

    (Step G1) O-alkylation    

This step is a step of obtaining compound (G-III) from compound (G-I) by performing O-alkylation using compound (G-II). This step can be performed in the same manner as step B4.

    (Step G2) Reduction of nitro    

This step is a step of obtaining the compound (G-IV) from the compound (G-III) using iron powder and ammonium chloride. As a reaction solvent, ethanol, water, acetic acid, etc. can be used. The reaction temperature is usually about 0 to 150 ° C, and the reaction time is about 1 hour to 3 days.

    (Step G3) Introduction of protecting group    

This step is a step of obtaining compound (G-V) from compound (G-IV) using pyridine and 4-nitrobenzenesulfonyl chloride. The reaction solvent is not particularly limited as long as it is inert to the present reaction, but tetrahydrofuran, methylene chloride, or the like can be used. The reaction temperature is usually about 20 to 60 ° C, and the reaction time is usually about 0.5 to 24 hours. In addition to these conditions, this step can be performed by appropriately selecting the reaction conditions described in Wuts (P.G.M.Wuts) and Greene (T.W.Greene) and Greene's Protective Groups in Organic Synthesis (5th edition, 2014).

    [H law]    

The H method is a method for producing the compound (H-IV) (the compound (G-II) of the G method).

[Wherein R ⁴ represents the same meaning as above]

    (Step H1)    

This step is a step of obtaining compound (H-II) from compound (H-I) using diethyl carbonate in the presence of a base. Examples of the base include sodium hydride, lithium diisopropylamidamine, and the like. The reaction solvent is not particularly limited as long as it is inert to the present reaction, and examples thereof include tetrahydrofuran. The reaction temperature is usually about 0 to 70 ° C, and the reaction time is usually about 1 hour to 3 days.

    (H2 step) Reduction reaction    

This step is a step of obtaining a compound (H-III) from a compound (H-II) using a reducing agent.

Examples of the reducing agent include sodium borohydride and lithium borohydride. Examples of the reaction solvent include methanol, ethanol, water, tetrahydrofuran, and mixtures thereof. The reaction temperature is usually 0 to 70 ° C, and the reaction time is usually 0.5 to 24 hours.

    (Step H3) Introduction of protecting group    

This step is a step of obtaining compound (H-IV) from compound (H-III) by using tert-butyldiphenylchlorosilane in the presence of imidazole and 4-dimethylaminopyridine. In addition, this step can be performed by appropriately selecting the reaction conditions described in Wuts (P.G.M.Wuts) and Greene (T.W.Greene), Greene's Protective Groups in Organic Synthesis (5th edition, 2014).

    [I Act]    

Method I produces compound (I-IV) (Method B (BV), Method E (EV), Method K (K-VI), Method O (O-III), Method P Method of compound (PI), compound (Q-II) of method Q or compound (S-II) of method S) or compound (IV) (compound (S-II) of method S)).

[Wherein R ¹ to R ^{3 have} the same meanings as above, and L represents halogen, methanesulfonyloxy or p-toluenesulfonyloxy]

    (Step I1) Condensation reaction    

This step is a step of obtaining compound (I-II) from compound (I-I) using N, O-dimethylhydroxylamine hydrochloride and a condensing agent in the presence of a base.

Examples of the base include triethylamine and diisopropylethylamine. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), 1,1'-carbonyldiimidazole (CDI), and the like. The reaction solvent is not particularly limited as long as it is inert to the reaction, but examples include N, N-dimethylformamide, dimethylacetamide, dichloromethane, and 1,2-dichloroethane. , Chloroform, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, or a mixture thereof. The reaction temperature is usually from room temperature to 120 ° C, and the reaction time is usually from 0.5 to 24 hours.

    (Step I2) Addition of organometallic reagent    

This step is a step of obtaining a compound (I-III) from a compound (I-II) by using a corresponding organometallic reagent (R ² -M; M represents a metal). Examples of the organometallic reagent include organolithium reagent (M = Li), organic magnesium (Grignard) reagent (M = MgX; X represents halogen), and organocerium reagent (M = CeX ₂ ). The reaction solvent is not particularly limited as long as it is inert to the present reaction, and examples thereof include diethyl ether, tetrahydrofuran, and toluene. The reaction temperature is usually about -78 to 60 ° C, and the reaction time is 0.5 to 24 hours.

    (Step I3)    

This step is a step of obtaining the compound (I-IV) from the compound (I-III) using any one of the following two steps.

(Step of obtaining a second-order alcohol (when R ³ = H))

This step is a step of obtaining a compound (I-IV) from a compound (I-III) using an asymmetric reducing agent.

Examples of the asymmetric reducing agent include optical activity of free (S) or (R) -5,5-diphenyl-2-methyl-3,4-propanol-1,3,2-oxaboridine Corey-Baksh-Shibata reducing agent prepared by oxaboridine and borane. This step can be performed in the same way as step D2.

(Step for obtaining a third-order alcohol (when R ³ = C1-C6 alkyl group)

This step is a step of obtaining a compound (I-IV) from a compound (I-III) using an organometallic reagent (R ³ -M; M represents a metal). This step can be performed in the same manner as step I2.

    (Step 4) halogenation or sulfonylation         (Sulfonylated)    

This step is a step of obtaining a compound (I-V) from a compound (I-IV) by using a sulfonylated reagent in the presence of a base. Examples of the base include pyridine, 4-dimethylaminopyridine, triethylamine, and diisopropylethylamine. Examples of the sulfonylation reagent include methanesulfonium chloride and p-toluenesulfonium chloride. The reaction solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include tetrahydrofuran, dichloromethane, and 1,2-dichloroethane. The reaction temperature is usually about -78 to 60 ° C, and the reaction time is about 0.5 to 24 hours.

    (Halogenated)    

This step is a step of obtaining a compound (I-V) from a compound (I-IV) using a halogenated reagent. Examples of the halogenated reagent include a combination of carbon tetrabromide, N-bromosuccinimide or bromine, and triphenylphosphine. Examples of the reaction solvent include acetonitrile, methylene chloride, and dichloroethane. The reaction temperature is usually about -40 to 50 ° C, and the reaction time is about 0.5 to 24 hours.

    [J 法]    

Method J manufacture compound (J-II) (Method B (BV), Method E (EV), Method K (K-VI), Method O (O-III), Method P Method of compound (PI), compound (Q-II) of method Q or compound (S-II) of method S) or compound (J-III) (compound (S-II) of method S).

[Wherein R ¹ to R ^{3 have} the same meanings as above, and L represents halogen, methanesulfonyloxy or p-toluenesulfonyloxy]

    (Step J1) Addition of organometallic reagent    

This step is a step of obtaining a compound (J-II) from a compound (J-I) using an organometallic reagent. This step can be performed in the same manner as step I2.

    (Step J2) Halogenation or sulfonylation    

This step is a step of obtaining a compound (J-III) from a compound (J-II) by using a sulfonating reagent in the presence of a halogenated reagent or a base. This step can be performed in the same manner as step I4.

    [K Method]    

The K method is a method for producing a compound (K-VII) (a compound equivalent to the compound (A-I) of the A method).

[In the formula, R ¹ to R ⁵ represent the same meaning as described above, and R represents a C1-C6 alkyl group or a C1-C6 alkylcarbonyl group. ]

    (Step K1) Deprotection    

This step is a step of obtaining the compound (K-II) by removing the Boc group from the compound (K-I). This step can be performed in the same manner as in step B1.

    (Step K2) Introduction of a substituent on a nitrogen atom    

This step is a step of obtaining a compound (K-III) by introducing a substituent on a nitrogen atom from the compound (K-II). This step can be performed in the same manner as the above step B3.

    (Step K3) Deprotection    

This step is a step of obtaining compound (K-IV) by removing 2-nitrobenzenesulfonyl from compound (K-III). This step can be performed in the same manner as the step C3.

    (Step K4) Introduction of a substituent on a nitrogen atom    

This step is a step of obtaining a compound (K-V) by introducing a substituent on a nitrogen atom from the compound (K-IV). This step can be performed in the same manner as step B3.

    (K5 step) O-alkylation    

This step is a step of obtaining a compound (K-VII) by subjecting the compound (K-V) to O-alkylation. This step can be performed in the same manner as step B4.

    [L Method]    

The L method is a method for producing a compound (L-V) (a compound of the K method (K-I)).

[Wherein R ⁴ represents the same meaning as above]

    (L1 step) Alkylation reaction    

This step is a step of obtaining a compound (L-II) from a compound (L-I) using a 2-bromo-1- (4-hydroxyphenyl) ethanone derivative in the presence of a base.

Examples of the base include triethylamine, diisopropylethylamine, and potassium carbonate. The reaction solvent is not particularly limited as long as it is inert to the present reaction, and examples thereof include tetrahydrofuran, 1,4-bis Alkane, acetonitrile, dichloromethane, N, N-dimethylformamide, or a mixture thereof. The reaction temperature is usually about 0 to 100 ° C, and the reaction time is usually about 0.5 to 24 hours.

    (L2 step) Asymmetric reduction    

This step is a step of obtaining a compound (L-III) from a compound (L-II) using an asymmetric reducing agent. This step can be performed in the same manner as step D2.

    (Step L3) Deprotection    

This step is a step of obtaining a compound (L-IV) by removing a protective group from the compound (L-III). This step can be performed in the same manner as the C1 step.

    (L4 step) Cyclization reaction (light extension reaction)    

This step is a step of obtaining a compound (L-V) from a compound (L-IV) by using a phosphine and an azodicarboxylate or azodimethylformamide. This step can be performed in the same manner as in the two steps.

    [M Method]    

The M method is a method for producing a compound (M-IV) (a compound equivalent to the compound (A-I) of the A method).

[In the formula, R ¹ to R ^{5 have} the same meanings as above, and R represents a C1-C6 alkyl group. ]

    (Step M1) Removal of the protecting group    

This step is a step of obtaining a compound (M-II) by removing a protecting group from the compound (M-I). This step can be performed in the same manner as the step E3.

    (Step M2) Introduction of a substituent on a nitrogen atom    

This step is a step of obtaining a compound (M-III) by introducing a substituent on a nitrogen atom from the compound (M-II).

This step can be performed in the same manner as the above step B3.

    (Step M3) Reduction reaction of amido group    

In this step, diethyl 1,4-dihydro-2,6-dimethyl-3,5-picolinate (Hantzsch ester) and trifluoromethanesulfonic anhydride are used to obtain a compound (M-III) M-IV). The reaction solvent is not particularly limited as long as it is inert to the present reaction, and examples thereof include diethyl ether, tetrahydrofuran, and 1,4-dioxane. Alkane, benzene, toluene, methylene chloride, chloroform, or a mixture thereof. The reaction temperature is usually about -20 ° C to 100 ° C, and the reaction time is about 0.5 to 24 hours.

    [N Method]    

The N method is a method for producing a compound (N-IV) (M compound (M-I)).

[In the formula, R ¹ to R ^{4 have} the same meanings as described above, and R represents a C1-C6 alkyl group. ]

    (Step N1) Amidation reaction    

This step is a step of obtaining a compound (N-III) from a compound (N-I) using a condensing agent in the presence of a base. This step can be performed under the same conditions as in step A2.

    (N2 step) Cyclization reaction (light extension reaction)    

This step is a step of obtaining a compound (N-IV) from a compound (N-III) using a phosphine and an azodicarboxylate or azodimethylformamide. This step can be performed in the same manner as the step C2.

    [O method]    

The O method is a method for producing a compound (O-VI) (a compound of the N method (N-II)).

[In the formula, R ¹ to R ^{4 have} the same meanings as above, and R represents the C1-C6 alkyl group. ]

    (Step O1) Alkylation    

In this step, 2-bromo-1- (4-hydroxyphenyl) ethanone derivative (OI) is used. After C1-C6 alkylamine (R-NH ₂ ) is alkylated, it is used in the presence of a base. A step of obtaining a compound (O-II) by trifluoroacetic anhydride being N-trifluoroacetamidated. Examples of the base include triethylamine and diisopropylethylamine. The reaction solvent is not particularly limited as long as it is inert to the present reaction, and examples thereof include tetrahydrofuran, 1,4-bis Alkane, dichloromethane, or a mixture thereof. The reaction temperature is usually about 0 to 60 ° C, and the reaction time is usually about 0.5 to 12 hours.

    (O2 step) O-alkylation    

This step is a step of obtaining a compound (O-IV) by subjecting the compound (O-II) to O-alkylation. This step can be performed in the same manner as step B4.

    (Step O3) Asymmetric reduction    

This step is a step of obtaining a compound (O-V) from a compound (O-IV) using an asymmetric reducing agent. This step can be carried out in the same manner as step D2. As the asymmetric reducing agent, it is preferable to use (R) -5,5-diphenyl-2-methyl-3,4-propanol-1,3 Modified by 2,2-oxaboridine and borane dimethyl sulfide.

    (Step O4) Deprotection    

This step is a step of obtaining a compound (O-VI) from a compound (O-V) using an alkaline aqueous solution. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate. The solvent is not particularly limited as long as it does not inhibit the reaction, but examples thereof include methanol, ethanol, tetrahydrofuran, dimethoxyethane, acetonitrile, and mixtures thereof. The reaction temperature is usually about 20 to 100 ° C, and the reaction time is usually 0.5 to 12 hours. This step can be performed by appropriately selecting the reaction conditions described in Wuts (P.G.M.Wuts) and Greene (T.W.Greene) and Greene's Protective Groups in Organic Synthesis (5th edition, 2014).

    [P method]    

The P method is a method for producing a compound (P-II) (optically active alcohol (I-IV) or (J-II)).

[Wherein R ¹ to R ³ represent the same meaning as above]

    (Step P1) Optical segmentation    

In this step, the compound (PI) is condensed with an optically active amino acid derivative to be converted into the corresponding ester. After the non-mirromeric isomers obtained are separated by chromatography, the ester having the desired stereochemistry is converted. A step of obtaining an optically active compound (P-II) by hydrolysis. As an optically active amino acid derivative, N-Boc prolinic acid of L-form or D-form is preferably mentioned. The esterification reaction in this step can use 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), 1,1'-carbonyldiimidazole (CDI), etc. Condensation agent. In the present reaction, an organic base such as 4-dimethylaminopyridine is advantageous in making the reaction proceed smoothly. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but examples include N, N-dimethylformamide, dimethylacetamide, dichloromethane, and 1,2-dichloro Ethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, or a mixture thereof. The reaction temperature is usually from room temperature to 120 ° C, and the reaction time is usually from 0.5 to 24 hours. After the esterification reaction and the separation step using chromatography, the hydrolysis reaction system in this step can use 1 equivalent or an excess of an alkaline aqueous solution. Examples of the base include lithium hydroxide, sodium hydroxide, and potassium hydroxide And other inorganic bases. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but examples thereof include methanol, ethanol, tetrahydrofuran, dimethoxyethane, acetonitrile, and mixtures thereof. The reaction temperature is usually about 0 to 60 ° C, and the reaction time is usually about 0.5 to 12 hours.

    [Q 法]    

The Q method is a method for producing a compound (Q-V) (a compound equivalent to the compound (A-I) of the A method).

[Wherein R ¹ to R ⁵ represent the same meaning as above]

    (Q1 step) O-alkylation    

This step is a step of obtaining a compound (Q-III) by subjecting the compound (Q-I) to O-alkylation. This step can be performed in the same manner as step B4.

    (Step Q2) Deprotection    

This step is a step of obtaining the compound (Q-IV) by removing the Boc group of the compound (Q-III). This step can be performed in the same manner as step B1.

    (Step Q3) Introduction of a substituent on a nitrogen atom    

This step is a step of obtaining a compound (Q-V) by introducing a substituent on a nitrogen atom from the compound (Q-IV). This step can be performed in the same manner as the above step B3.

    [R Method]    

The R method is a method for producing a compound (R-IV) (a compound of the Q method (Q-I)).

[Wherein R ⁴ represents the same meaning as above]

    (Step R1) Addition reaction to alkyne    

This step is carried out from compound (RI) in the presence of a base using the desired arylboronic acid (representing the use of 4- (benzyloxy) phenylboronic acid in which phenyl is substituted with substituent R ⁴ in the formula Case.), A rhodium catalyst and a phosphine ligand to obtain a compound (R-II). Examples of the rhodium catalyst include a hydroxy (cyclooctadiene) rhodium (I) dimer, a chloro (1,5-cyclooctadiene) rhodium (I) dimer, and acetopyruvate bis (ethylene). Rhodium (I) and the like. Examples of the phosphine ligand include 1,3-bis (diphenylphosphine) propane, 1,4-bis (diphenylphosphine) butane, 1,1'-bis (diphenylphosphine) ferrocene , 2,2'-bis (diphenylphosphine) -1,1'-biperylene and the like. Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, lithium hydroxide, and sodium hydroxide. The reaction solvent is not particularly limited as long as it does not hinder the reaction, but examples include 1,4-bis Alkane, 1,2-dimethoxyethane, water, toluene, or a mixture thereof. The reaction temperature is usually about 20 to 100 ° C, and the reaction time is usually about 1 to 24 hours.

    (R2 step) Deprotection and hydrogenation    

This step is a step of obtaining a compound (R-III) from a compound (R-II) by removing a benzyl group and hydrogenating an olefin using a metal catalyst under a hydrogen environment. This step can be performed in the same manner as step B2.

    (Step R3) Cyclization reaction    

This step is a step of obtaining a compound (R-IV) from a compound (R-III) by using a phosphine and an azodicarbonate or azodimethanamine. This step can be performed in the same manner as the step C2.

    [S law]    

The S method is a method for producing a compound (S-V) (a compound corresponding to the compound (A-I) of the A method).

[Wherein R ¹ to R ^{5 have} the same meanings as above, and L represents a halogen atom, methanesulfonyloxy or p-toluenesulfonyloxy]

    (S1 step) O-alkylation         (In the case of photo-delay reaction)    

This step is a step of obtaining the compound (S-III) from the compound (S-I) by O-alkylation using an alcohol (S-II). This step can be performed in the same manner as step B4.

    (When using alkylated reagents)    

This step is a step of obtaining a compound (S-III) by subjecting the compound (SI) to O-alkylation using an alkylation reagent (S-II ') in the presence of a base. As the alkylation reagent, an alkyl sulfonate prepared by the I method or the J method can be used. As the base, organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate and sodium carbonate can be used. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but examples thereof include tetrahydrofuran, 1,4-bis Alkane, acetonitrile, dichloromethane, N, N-dimethylformamide, dimethylmethane, or a mixture thereof, etc. The reaction temperature is usually about 0 to 100 ° C, and the reaction time is usually 0.5 to 24 hours about.

    (Step S2) Deprotection    

This step is a step of obtaining a compound (S-IV) by removing the Boc group from the compound (S-III). This step can be performed in the same manner as step B1.

    (Step S3) Introduction of a substituent on a nitrogen atom    

This step is a step of obtaining a compound (S-V) by introducing a substituent on a nitrogen atom from the compound (S-IV). This step can be performed in the same manner as in the above step B3.

    [T law]    

The T method is a method for producing a compound (T-V) (S-I compound (S-I)).

[Wherein R ⁴ represents the same meaning as above]

    (Step T1) Coupling reaction    

This step is a step of obtaining a compound (T-III) from a compound (TI) using an organic zinc reagent and a metal catalyst. Examples of the metal catalyst include a palladium catalyst and a nickel catalyst. Examples of the palladium catalyst include (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphine) ferrocene] dichloropalladium, ginsyl (dibenzylideneacetone) dipalladium, and palladium acetate. , Acetoacetone palladium, or bis (triphenylphosphine) palladium dichloride, etc., as the nickel catalyst, [1,1'-bis (diphenylphosphine) ferrocene] nickel dichloride, Or bis (triphenylphosphine) nickel dichloride and the like. Good results may be obtained when lithium chloride is added. Organic zinc reagents are obtained from zinc powder activated with iodine, trimethylsilyl chloride, or the like, and alkyl iodide (T-II). The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but examples thereof include tetrahydrofuran, 1,4-bis Alkane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, toluene or a mixture of these and the like. The reaction temperature is usually about 20 to 150 ° C, and the reaction time is usually about 1 hour to 3 days.

    (Step T2) Deprotection    

This step is a step of obtaining a compound (T-IV) from a compound (T-III) by removing a benzyl group using a metal catalyst under a hydrogen environment. This step can be performed in the same manner as step B2.

    (T3 step) Cyclization reaction    

This step is a step of obtaining a compound (T-V) from a compound (T-IV) by using a phosphine and an azodicarbonate or azodimethanamine. This step can be performed in the same manner as the step C2.

    [U Method]    

The U method is a method for producing a compound (U-V) (a compound of the T method (T-II)).

[Wherein R ⁴ represents the same meaning as above]

    (Step U1) Introduction of asymmetric auxiliary base    

This step is a step of obtaining a compound (U-II) by introducing an asymmetric auxiliary group into the compound (UI). Initially, the compound (UI) was converted into the corresponding acid chloride by using the catalytic amounts of N, N-dimethylformamide and chloramphenicol in dichloromethane. The reaction temperature is about 20 to 40 ° C, and the reaction time is about 1 to 12 hours. Second, (R) -4-benzyl-2- Oxazolidinone was treated with n-butyllithium at -78 ° C, and the above acid chloride was added, and reacted at about 20 to 40 ° C to obtain compound (U-II). The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but tetrahydrofuran and the like are preferred, and the reaction time is usually about 0.5 to 12 hours.

    (U2 step) Alkylation reaction    

This step is a step of obtaining compound (U-III) from compound (U-II) using 2- (benzyloxy) ethyltrifluoromethanesulfonate in the presence of a base. As the base, sodium bis (trimethylsilyl) fluorenamine, lithium bis (trimethylsilyl) fluorenamine, lithium diisopropylfluorenamine, and the like are used. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but examples thereof include diethyl ether, tetrahydrofuran, and the like. The reaction temperature is usually about -78 to 20 ° C, and the reaction time is about 0.5 to 12 hours.

    (U3 step) Removal of asymmetric auxiliary group    

This step is a step of obtaining a compound (U-IV) from a compound (U-III) using a reducing agent. Examples of the reducing agent include lithium aluminum hydride and lithium borohydride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but examples thereof include methanol, ethanol, water, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and the like. Mixture and so on. The reaction temperature is usually about 0 to 60 ° C, and the reaction time is usually about 1 to 24 hours.

    (U4 step) Iodization    

This step is a step of obtaining a compound (U-V) from a compound (U-IV) using an iodinated reagent and triphenylphosphine in the presence of a base. Examples of the iodination reagent include iodine and N-iodosuccinic acid imine. Examples of the base include imidazole and pyridine. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but examples thereof include diethyl ether, acetonitrile, methylene chloride, hexane, toluene, N, N-dimethylformamide, or other solvents. And so on. The reaction temperature is usually about 0 to 100 ° C, and the reaction time is usually about 1 to 24 hours.

    [V method]    

Method V is a method for producing compound (V-III) (compound (A-III) of method A).

[R ⁶ to R ^{7 have} the same meaning as above, and X represents a halogen atom]

    (Step V1) Cross-coupling reaction    

This step is in the presence of a palladium catalyst or a nickel catalyst, using (i) boric acid or borate (M = B (OH) ₂ or B (OR) ₂ ), a base, and (ii) an organotin test reagent ( M = SnR ₃ ), or (iii) an organozinc reagent (M = ZnX), and a step of obtaining compound (V-II) from compound (VI). The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but examples thereof include methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane. Alkane, water, N, N-dimethylformamide, dimethylmethane, benzene, toluene, xylene, or a mixture thereof. Examples of the palladium catalyst include (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphine) ferrocene] dichloropalladium, ginsyl (dibenzylideneacetone) dipalladium, and palladium acetate. , Acetoacetone palladium, or bis (triphenylphosphine) palladium dichloride. Examples of the nickel catalyst include [1,1'-bis (diphenylphosphine) ferrocene] nickel dichloride, bis (triphenylphosphine) nickel dichloride, and the like. Examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), and 1,5-diazepine. Organic bases such as heterobicyclo [4.3.0] -5-nonene (DBN); potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, or sodium phosphate Inorganic base. The reaction temperature is usually about 20 to 150 ° C, and the reaction time is about 1 hour to 2 days.

    (Step V2) Deprotection    

This step is a step of removing the protective group from the compound (V-II) to obtain the compound (V-III) or a salt thereof. Various conditions can be applied depending on the protective group used. It can be performed by appropriately selecting the reaction conditions described in Wuts (P.G.M.Wuts) and Greene (T.W.Greene), Greene's Protective Groups in Organic Synthesis (5th edition, 2014).

    [W Act]    

The W method is a method for producing a compound (W-V).

[Wherein R ⁶ to R ^{7 have} the same meanings as above, and X represents a halogen atom]

    (Step W1) Coupling reaction    

This step is a step of obtaining a compound (W-II) from a compound (W-I) using a coupling reaction. This step can be performed in the same manner as step V1.

    (Step W2) Sandmeyer reaction    

This step is a step of obtaining a compound (W-III) from a compound (W-II) using a nitrite or a nitrite and a copper salt. Examples of the nitrite or nitrite include sodium nitrite, tertiary butyl nitrite, and isoamyl nitrite. Examples of the copper salt include copper (II) bromide. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but examples thereof include methanol, ethanol, water, acetonitrile, and mixtures thereof. The reaction temperature is usually about 0 to 80 ° C, and the reaction time is usually about 0.5 to 24 hours.

    (Step W3) Coupling    

This step is a step of obtaining the compound (W-IV) from the compound (W-III) using an organic zinc compound and a metal catalyst. The organic zinc compound can be prepared from methyl (2R) -2- (tertiary butoxycarbonylamino) -3-iodopropionate. This step can be performed in the same manner as the T1 step.

    (Step W4) Deprotection    

This is a step of removing a Boc group from a compound (W-IV) to obtain a compound (W-V) or a salt thereof. This step can be performed in the same manner as step B1.

    (Dosing Form)    

Administration can be by oral administration using tablets, pills, capsules, granules, powders, liquids, etc .; or by intra-articular, intravenous, intramuscular injections, suppositories, eye drops, eye ointments, Any form of parenteral administration such as transdermal solution, ointment, transdermal patch, transmucosal solution, transmucosal patch, inhalant, etc.

For the solid composition for oral administration, tablets, powders, granules, and the like can be used. This solid composition contains one or more active ingredients and at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, poly Vinyl pyrrolidone, and / or magnesium aluminometasilicate. This composition may contain an inert additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a dissolution aid in accordance with a general method. Lozenges or pills can be coated with sugar-coated or gastric-coated or enteric-coated substances as necessary.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, etc., and include generally used inert diluents such as pure water or ethanol. In addition to the inert diluent, the liquid composition may contain auxiliary agents such as co-solvents, wetting agents, suspending agents, sweeteners, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline solution. As non-aqueous solvents, for example, vegetable oils such as propylene glycol, polyethylene glycol, or olive oil; alcohols such as ethanol; or polysorbate 80 and the like. Such a composition may further contain an isotonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, or a dissolution aid. These are, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or sterilization by irradiation with radiation. In addition, these can also be used to produce a sterile solid composition that is dissolved or suspended in sterile water or a sterile vehicle for injection before use.

External preparations include ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments, and the like. These dosage forms contain generally used ointment bases, emulsion bases, aqueous or non-aqueous liquids, suspensions, emulsions and the like. Examples of the ointment or emulsion base include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hardened castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, laurel Alcohol, sorbitan sesquioleate and the like.

Transmucosal agents such as inhalants and nasal agents can be used in the form of a solid, liquid, or semi-solid, and can be produced according to a conventionally known method. For example, well-known excipients may be appropriately added, and a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, or a thickener may be appropriately added. Administration is by use of appropriate devices for inhalation or insufflation. For example, a known device or a nebulizer for metered administration of an inhaler or the like may be used to administer the compound alone or as a powder of a formulated mixture, or in combination with a pharmaceutically acceptable carrier as a solution or suspension. Dry powder inhalers and the like can be administered for single or multiple administrations, and dry powder or powder-containing capsules can be used. Alternatively, an appropriate propellant is used, for example, in the form of a pressurized aerosol spray of a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.

    (Dosage)    

In the case of oral administration, the daily dose is about 0.001-100 mg / kg per unit weight, preferably 0.1-30 mg / kg, more preferably 0.1-10 mg / kg. It is appropriate to use it once, Or two or more times. In the case of intravenous administration, the daily dose is approximately 0.0001-10 mg / kg per unit body weight, which is appropriate once a day or multiple times. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg per unit weight is administered once a day or several times. The administration amount is appropriately determined in consideration of each situation in consideration of symptoms, age, and sex.

    (Combined)    

In the present invention, various therapeutic or prophylactic agents for diseases which are considered to be effective can be used in combination. The combined use can be administered simultaneously, or separately and continuously or at desired time intervals. The preparations to be administered at the same time can be admixtures or individual preparations.

    (Preparation Example 1) powder    

A powder was obtained by mixing 5 g of the compound of the present invention or a pharmacologically acceptable salt thereof, 895 g of lactose, and 100 g of corn starch with a mixer.

    (Preparation Example 2) Granules    

After mixing 5 g of the compound of the present invention or a pharmacologically acceptable salt thereof, 865 g of lactose, and 100 g of low-substituted hydroxypropyl cellulose, 300 g of a 10% hydroxypropyl cellulose aqueous solution was added and kneaded. Granulation was performed using an extruder granulator and dried to obtain granules.

    (Formulation Example 3) Lozenge    

5 g of the compound of the present invention or a pharmacologically acceptable salt thereof, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and 1 g of magnesium stearate are mixed in a mixer, and then tableted by a tableting machine to obtain tablets Agent.

The pharmacological activity of the compound of the present invention or a pharmacologically acceptable salt thereof was confirmed by the following test.

    (Test Example 1) Cell test using cAMP as an index    

The activity of the GLP-1 receptor agonist is to utilize the cAMP function of CHO-K1 cells (cAMP Hunter (registered trademark) CHO-K1 GLP1R Gs Cell Line) (DiscoverX, # 95-0062C2) expressing the human GLP-1 receptor. Evaluation to determine. GLP-1 receptor-expressing cells (5,000-10,000 cells per 0.1 mL) were seeded on a 96-well plate with AssayComplete (registered trademark) Cell Plating 2 Reagent (DiscoverX, # 93-0563R2A). The cell line was cultured overnight at 37 ° C, 95% O ₂ , 5% CO ₂ in an incubator, then the culture medium was removed, and the compound was treated with compounds on Hanks' Balanced Salt solution (HBSS) (LIFE TECHNOLOGIES) medium (100 μL final Cells at a concentration of 100 μM PDE inhibitor IBMX, 0.1% BSA, 1% DMSO) were treated and cultured in an incubator for 1 hour. CAMP was quantified by reading chemiluminescence signals with Rubystar using a competitive immunoassay (cAMP-Gs HiRange kit, Cisbio) based on HTRF (registered trademark) technology. In addition, the EC50 of each compound was determined from the analysis of chemiluminescence, and Emax was determined by using the response curve of the amount of GLP-1. Table 1 shows the average EC50 (nM) and Emax (%) of the example compounds. The specificity of the GLP-1 receptor agonist for the GLP-1 receptor was confirmed by performing the same evaluation using a human glucagon receptor and a GIP receptor.

    (Experimental Example 2) Mouse Feeding Inhibition Test         (1) Use of animals    

Commercially available mice (C57BL / 6N mice, male, 8 to 10 weeks of age at the time of use, sold by Charles River, Japan) were used.

    (2) Experimental methods and results    

After mice were allowed to freely ingest solid feed (FR-2, Funabashi Farm Co., Ltd.) for more than one week and domesticated, they were domesticated and fed with a bait measurement device (FDM300SS, Melquest Co., Ltd.) with bait restriction function1 Zhou, fasted overnight by closing the electric door to block the access to the feed for testing. The rearing room is switched off at 7 pm and switched on at 12 am for 12 hours. The test compound (Example compound, Comparative compound 1 (the compound described in WO2009 / 111700 Example 87) or Comparative Compound 2 (the compound described in WO2010 / 114824 Example 216)) was prepared by using 0.5% methyl cellulose (and Kwang Chun Pharmaceutical Co., Ltd.) or sodium carbonate ‧ sodium bicarbonate mixed solution, and polyethylene glycol 400 ‧ Tween 80 is added to prepare it if necessary. The prepared administration solution (control group (administration of vehicle containing no test compound) and test compound group) was administered orally to 5 to 6 mice in each group. Thirty minutes after the test compound was administered, the electric gear door was opened, and the amount of bait consumed 24 hours after re-feeding was measured and analyzed using software for bait control and bait measurement devices.

When the compounds of Examples 9, 11, 12, 39, 48, 62, and 64 and the comparative compound 1 and the comparative compound 2200 mg / kg were orally administered, the feeding inhibition rate (%) compared to the control group was The following calculation formula is calculated and shown in Table 2.

Inhibition rate of food intake (%) = (amount of bait in the control group-the amount of bait in the compound administration group of each example) / the amount of bait in the control group x 100

From the results of Test Example 2, it was found that the compound of the present invention exhibited a significant food-inhibiting effect. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof can be administered to mammals (especially humans) for the purpose of preventing or treating obesity, and is useful as medicine.

    (Test Example 3) Oral glucose load test in mice         (1) Use of animals    

Commercially available mice (C57BL / 6N mice, male, 7-9 weeks of age at the time of use, sold by Charles River (stock) in Japan) were used.

    (2) Experimental methods and results    

Mice were allowed to freely ingest solid feed (FR-2, Funabashi Farm Co., Ltd.) for more than one week, and after acclimatization, they were fasted overnight and used for testing. The rearing room is switched off at 7 pm and switched on at 12 am for 12 hours. The test compound (example compound, comparative compound 1 or comparative compound 2) was prepared by using 0.5% methyl cellulose (Wako Pure Chemical Industries, Ltd.) or a mixed solution of sodium carbonate and sodium bicarbonate, and added as necessary. Polyethylene glycol 400‧Tween80. The prepared dosing solution (control group (administered vehicle containing no test compound) and test compound group) was prepared, and 5 to 6 mice in each group were treated with the compound of Example 50 mg / kg to compare Compound 1 And Comparative Compound 2 was administered orally at 200 mg / kg. The glucose load was administered orally to a glucose solution (Otsuka sugar solution) at a dosage of 2 g / kg 30 minutes after the test compound was administered.

Blood was collected from the tail vein immediately before glucose administration and at 5, 15, 30, 60, and 120 minutes after administration, and blood glucose was measured. Table 3 shows the results of the area under the curve (AUC) of the change (Δ) of the blood glucose level immediately before the administration of glucose. From the results, it was found that the compound of the present invention significantly lowered the blood glucose level.

From the results of Test Example 3, it is understood that the compound of the present invention exhibits a significant blood glucose lowering effect. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof can be administered to mammals (especially humans) for the purpose of preventing or treating diabetes, and is useful for medicine.

    [Example]    

Hereinafter, the present invention will be described in more detail with reference examples and examples, but the scope of the present invention is not limited to these examples.

Dissolution in column chromatography in the examples was performed under the observation of TLC (Thin Layer Chromatography, thin layer chromatography). Observed by TLC, using a silicone gel 60F254 made by Merck as the TLC plate, using the dissolution solvent of column chromatography as the developing solvent, and using a UV detector as the detection method. The silica gel for the column uses the same Silicone SK-85 (230-400 mesh) manufactured by Merck or Fuji Silysia Chemical Chromatorex NH (200-350 mesh). In addition to the usual column chromatography, an automatic chromatography device (Purif-α2 or Purif-espoir2) from SHOKO SCIENCE CO., LTD. Is suitably used. The dissolution solvent was determined based on TLC observation.

The abbreviations used in the examples have the following meanings.

mg: milligram, g: gram, μL: microliter, mL: milliliter, mmol: millimolar, mol: mole, wt%: weight percent, MHz: megahertz.

In the following examples, a nuclear magnetic resonance (hereinafter, 1H NMR) spectrum uses tetramethylsilane as a reference material, and a chemical shift value is described in a δ value (ppm). The split pattern is represented by a single line as s, a double line as d, a triple line as t, a quartet line as q, a multiple line as m, and a broad peak as br. Mass analysis (hereinafter, MS) was performed by EI (Electron Ionization) method, ESI (Electronspray Ionization) method, or FAB (Fast Atom Bombardment) method.

    Reference example 1    

3-{[tertiary butyl (diphenyl) silyl] oxy} -1- {4-[(prop-2-en-1-yl) oxy] phenyl} propanol

    (1a) 1- {4-[(prop-2-en-1-yl) oxy] phenyl} ethane-1-one    

To a solution of 4'-hydroxyacetophenone (1.00 g, 7.34 mmol) in acetone (24.5 mL), add allyl bromide (756 μL, 8.81 mmol) and potassium carbonate (1.52 g, 11.0 mmol), and heat to 65 ° C and stirred for 2.5 hours. After the reaction solution was allowed to cool to room temperature, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20) to obtain 1.32 g of the title compound (quantitative) as a colorless oily substance.

    (1b) Ethyl 3- {4-[(prop-2-en-1-yl) oxy] phenyl} propanoate    

To a suspension of diethyl carbonate (340 μL, 2.84 mL) and sodium hydride (60 wt%, 136 mg, 3.12 mmol) in tetrahydrofuran (5 mL) was added 1- {4-[(propyl) obtained in Reference Example 1 (1a). 2-en-1-yl) oxy] phenyl} ethane-1-one (500 mg, 2.84 mmol) was stirred at 70 ° C. for 1 hour and then at room temperature for 16 hours. Diethyl carbonate (340 μL, 2.84 mL) and sodium hydride (60 wt%, 136 mg, 3.12 mmol) were further added, and the mixture was stirred at room temperature for 4 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and extracted with ethyl acetate (× 2). The organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20) to obtain 335 mg of the title compound as a yellow oily substance (yield 48%).

    (1c) 1- {4-[(prop-2-en-1-yl) oxy] phenyl} propane-1,3-diol    

Ethyl 3- pendantoxy-3- {4-[(prop-2-en-1-yl) oxy] phenyl} propanoate (320 mg, 1.37 mmol) obtained in Reference Example 1 (1b) To a methanol (5 mL) / tetrahydrofuran (2.5 mL) solution, sodium borohydride (155 mg, 4.10 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and extracted with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 90) to obtain 157 mg of the title compound as a colorless oily substance (yield 55%).

    (1d) 3-{[tertiary butyl (diphenyl) silyl] oxy} -1- {4-[(prop-2-en-1-yl) oxy] phenyl} propane-1- Alcohol    

N of 1- {4-[(prop-2-en-1-yl) oxy] phenyl} propane-1,3-diol (157 mg, 0.754 mmol) obtained in Reference Example 1 (1c), To a solution of N-dimethylformamidine (3 mL), imidazole (103 mg, 1.51 mmol), 4-dimethylaminopyridine (9 mg, 0.075 mmol), and tertiary butyl diphenylchlorosilane (232 μL, 0.905 mmol) and stirred at room temperature for 2 hours. Water was added to the reaction solution, and extracted with ethyl acetate (× 2). The organic layers were combined, washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25) to obtain 293 mg of the title compound as a colorless oily substance (yield 87%).

    Reference example 2    

(9S) -1-methyl-4- {4-[(prop-2-en-1-yl) oxy] phenyl} -1,2,3,4,7,8,9,10-octa Hydrogen [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester

    (2a) (3S) -7-Hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride    

To a solution of (3S) -7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (47.8 g, 247 mmol) in methanol (380 mL) was added 4N-hydrochloric acid / 1,4-di The alkane solution (500 mL) was heated under reflux at 90 ° C for 5 hours. After the reaction solution was allowed to cool to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate / n-hexane and filtered to obtain 50.4 g of the title compound as a white solid (yield 84%).

    (2b) (3S) -7-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

Tetrahydrofuran (860 mL) of (3S) -7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride (126 g, 517 mmol) obtained in Reference Example 2 (2a) To the water / water (430 mL) mixed solution, triethylamine (86 mL, 620 mmol) and di-tertiary-butyl dicarbonate (131 mL, 569 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Analytical (n-hexane: ethyl acetate = 90: 10-65: 35) was purified to obtain 106 g of the title compound as a yellow oily substance (yield 67%).

    (2c) (3S) -7-hydroxy-6-nitro-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -7-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-formaldehyde obtained in Reference Example 2 (2b) under a nitrogen atmosphere In a dichloromethane (30 mL) solution of a base ester (6.00 g, 19.5 mmol), fuming nitric acid (97 wt%, 896 μL, 21.5 mmol) was carefully added dropwise while maintaining at 15 to 25 ° C., and stirred for 15 minutes. minute. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20-70: 30). Thus, 2.27 g of the title compound was obtained as a yellow solid (yield: 33%).

    (2d) (3S) -7- (3-{[tertiary butyl (diphenyl) silyl] oxy} -1- {4-[(prop-2-en-1-yl) oxy] (Phenyl) propoxy) -6-nitro-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -7-hydroxy-6-nitro-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tertiary obtained in Reference Example 2 (2c) under nitrogen atmosphere Butyl 3-methyl ester (2.26 g, 6.41 mmol) and 3-{[tertiary butyl (diphenyl) silyl] oxy} -1- {4- [obtained in Reference Example 1 (1d) (Prop-2-en-1-yl) oxy] phenyl} propane-1-ol (3.15 g, 7.06 mmol) in a solution of tetrahydrofuran (64 mL), and under ice cooling, triphenylphosphine (3.36 g, 12.8 mmol) and bis (2-methoxyethyl) azodicarboxylate (3.00 g, 12.8 mmol), and stirred at room temperature for 16 hours. Diethyl ether was added to the reaction solution, washed with saturated brine-water (1: 1 mixed solution), and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20) to obtain 3.12 g of the title compound as a yellow amorphous substance (yield: 62%).

    (2e) (3S) -6-amino-7- (3-{[tertiary butyl (diphenyl) silyl] oxy) -1- {4-[(prop-2-ene-1- Yl) oxy] phenyl} propoxy) -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -7- (3-{[Tributyl (diphenyl) silyl] oxy} -1- {4-[(propyl- 2-en-1-yl) oxy] phenyl} propoxy) -6-nitro-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tertiarybutyl 3 -To a solution of methyl ester (3.12 g, 3.99 mmol) in ethanol (65 mL), water (32 mL), iron powder (2.23 g, 39.9 mmol), and ammonium chloride (214 mg, 3.99 mmol) were added and stirred at 80 ° C for 6 hour. The reaction solution was filtered through celite and washed with ethyl acetate. After ethyl acetate and water were added to the filtrate, the mixture was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40) to obtain 2.76 g of the title object as a pale yellow oily substance (yield: 92%).

    (2f) (3S) -7- (3-{[tertiary butyl (diphenyl) silyl] oxy} -1- {4-[(prop-2-en-1-yl) oxy] Phenyl} propoxy) -6-[(4-nitrobenzene-1-sulfonyl) amino] -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tri 3-butyl 3-methyl ester    

(3S) -6-amino-7- (3-{[tertiary butyl (diphenyl) silyl] oxy) -1- {4-[(propyl) obtained in Reference Example 2 (2e) -2-en-1-yl) oxy] phenyl} propoxy) -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (2.76 g, 3.68 mmol) in dichloromethane (12 mL), and under ice cooling, pyridine (355 μL, 4.41 mmol) and 4-nitrobenzenesulfonyl chloride (814 mg, 3.68 mmol) were added, and Stir for 2 hours. 1N-hydrochloric acid was added to the reaction solution, and extracted with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25) to obtain 2.74 g of the title compound as a yellow amorphous substance (yield: 80%).

    (2g) (3S) -7- (3-hydroxy-1- {4-[(prop-2-en-1-yl) oxy] phenyl} propoxy) -6-[(4-nitro Benzene-1-sulfonyl) amino] -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -7- (3-{[tertiary butyl (diphenyl) silyl] oxy) -1- {4-[(prop-2-ene- 1-yl) oxy] phenyl} propoxy) -6-[(4-nitrobenzene-1-sulfonyl) amino] -3,4-dihydroisoquinoline-2,3 (1H ) -Tetrahydrofuran (20 mL) of 2-tert-butyl 3-methyl dicarboxylate (2.74 g, 2.93 mmol), and tetrabutylammonium fluoride (1M-tetrahydrofuran solution, 3.22 mL, 3.22 mmol) was added, And stirred at room temperature for 16 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and extracted with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 30: 70) to obtain 1.82 g of the title compound (yield: 89%) as a yellow amorphous substance.

    (2h) (9S) -1- (4-nitrobenzene-1-sulfonyl) -4- {4-[(prop-2-en-1-yl) oxy] phenyl} -1,3 , 4,7,9,10-hexahydro [1,4] oxacridine [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl 9-methyl Ester    

(3S) -7- (3-hydroxy-1- {4-[(prop-2-en-1-yl) oxy] phenyl} propoxy obtained in Reference Example 2 (2g) under a nitrogen atmosphere ) -6-[(4-nitrobenzene-1-sulfonyl) amino] -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3- To a solution of methyl ester (1.82 g, 2.61 mmol) in tetrahydrofuran (52 mL) was added triphenylphosphine (2.74 g, 10.4 mmol) and bis (2-methoxyethyl) azodicarboxylic acid under ice cooling. The ester (2.44 g, 10.4 mmol) was stirred at room temperature for 5.5 hours. Diethyl ether was added to the reaction solution, washed with saturated brine-water (1: 1 mixed solution), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30) to obtain 1.82 g of the title compound (quantitative) as a yellow oily substance.

    (2i) (9S) -4- {4-[(prop-2-en-1-yl) oxy] phenyl} -1,3,4,7,9,10-hexahydro [1,4] Oxacridine [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl 9-methyl ester    

(9S) -1- (4-nitrobenzene-1-sulfonyl) -4- {4-[(prop-2-en-1-yl) oxy] obtained in Reference Example 2 (2h) Phenyl} -1,3,4,7,9,10-hexahydro [1,4] oxazepine [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tris To a solution of N-N-dimethylformamidine (40 mL) in grade butyl 9-methyl ester (1.22 g, 1.79 mmol), lithium hydroxide monohydrate (300 mg, 7.17 mmol) and hydrothioacetic acid were added. (249 μL, 3.58 mmol) and stirred at room temperature for 16 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50) to obtain 860 mg of the title compound (yield: 97%) as a white amorphous substance.

    (2j) (9S) -1-methyl-4- {4-[(prop-2-en-1-yl) oxy] phenyl} -1,3,4,7,9,10-hexahydro [1,4] oxacridine [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl 9-methyl ester    

(9S) -4- {4-[(prop-2-en-1-yl) oxy] phenyl} -1,3,4,7,9,10- obtained in Reference Example 2 (2i) Hexahydro [1,4] oxacridine [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl 9-methyl ester (860mg, 1.74mmol) To a solution of 2-dichloroethane (40 mL), paraformaldehyde (470 mg, 15.7 mmol), sodium triacetoxyborohydride (4.53 g, 21.4 mmol), and acetic acid (299 μL, 5.22 mmol) were sequentially added. Stir at 60 ° C for 3.5 hours. The reaction solution was left to cool to room temperature, and a saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40) to obtain 773 mg of the title compound as a colorless amorphous substance (yield 87%).

    (2k) (9S) -1-methyl-4- {4-[(prop-2-en-1-yl) oxy] phenyl} -1,2,3,4,7,8,9, 10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(9S) -1-methyl-4- {4-[(prop-2-en-1-yl) oxy] phenyl} -1,3 obtained in Reference Example 2 (2j) under a nitrogen atmosphere , 4,7,9,10-hexahydro [1,4] oxacridine [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl To a solution of the ester (773 mg, 1.52 mmol) in dichloromethane (25 mL), under ice cooling, trimethylsilane iodide (647 μL, 4.56 mmol) was added and stirred for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50-0: 100) to obtain 451 mg of the title compound (yield: 73%) as a white solid.

    Reference example 3    

(4R, 9S) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxyazepine [3 , 2-g] isoquinoline-9-carboxylic acid methyl ester

    (3a) (3S) -7-{[tertiary butyl (dimethyl) silyl] oxy} -6-nitro-3,4-dihydroisoquinoline-2,3 (1H) -di 2-tert-butyl 3-methyl formate    

(3S) -7-hydroxy-6-nitro-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tertiary obtained in Reference Example 2 (2c) under nitrogen atmosphere To a solution of butyl 3-methyl ester (10.0 g, 28.4 mmol) in dichloromethane (190 mL), under ice cooling, triethylamine (4.72 mL, 34.1 mmol) and 4-dimethylamino group were sequentially added. Pyridine (173 mg, 1.42 mmol) and tert-butyldimethylchlorosilane (4.71 g, 31.22 mmol) were stirred at room temperature for 2 hours. Saturated saline was added to the reaction solution, and the mixture was extracted with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0-80: 20) to obtain 13.7 g of a colorless oily substance. Title compound (quantitative).

    (3b) (3S) -6-amino-7-{[tertiary butyl (dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -di 2-tert-butyl 3-methyl formate    

2-tert-butyl 3-methyl (3S) -7-{[tertiary-butyl (dimethyl) silyl] oxy} -6- obtained in Reference Example 3 (3a) under a nitrogen atmosphere To a solution of nitro-3,4-dihydroisoquinoline-2,3 (1H) -diformate (27.3g, 58.4mmol) in ethanol (487mL), 10% palladium on carbon (wet, 50wt%, 6.22 g, 2.92 mmol), and stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-70: 30) to obtain 20.8 g of the title compound (yield 82) %) Obtained as a pale yellow viscous oily substance.

    (3c) (3S) -7-{[tertiary butyl (dimethyl) silyl] oxy} -6-[(4-nitrobenzene-1-sulfonyl) amino] -3,4 -Dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6-amino-7-{[tertiary butyl (dimethyl) silyl] oxy} -3,4-dihydroiso, obtained in Reference Example 3 (3b) under a nitrogen atmosphere In a solution of quinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (52.6 g, 120 mmol) in dichloromethane (600 mL), pyridine (11.62 mL) was sequentially added under ice cooling. 145 mmol) and 4-nitrobenzenesulfenyl chloride (32.0 g, 145 mmol), and stirred at room temperature for 3 hours. After the reaction solution was allowed to cool to room temperature, 1N-hydrochloric acid (140 mL, 145 mmol) was added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1-5: 1-3: 1) to obtain 60.0 g of the title compound as a pale yellow solid (yield 80%).

    (3d) (3S) -6-[[3- [4- (benzyloxy) phenyl] -3-sideoxypropyl} (4-nitrobenzene-1-sulfonyl) amino]- 7-{[tertiary-butyl (dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tertiary-butyl 3-methyl ester    

1- [4- (benzyloxy) phenyl] -2-propen-1-one (543mg, 2.28mmol) in ethanol (synthesized according to the description of Angewandte Chemie-International Edition, 2011, 50, 12335-12338) (8.8mL), (3S) -7-{[tertiary butyl (dimethyl) silyl] oxy} -6-[(4-nitrobenzene- 1-sulfofluorenyl) amino] -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tri-butyl 3-methyl ester (1.09 g, 1.75 mmol) and triethyl Amine (243 μL, 1.75 mmol), and stirred at 50 ° C. for 8 hours. Further, 1- (4-benzyloxyphenyl) -2-propen-1-one (125 mg, 0.526 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15-65: 35) to obtain 1.14 g of the title compound as a pale yellow amorphous substance (yield 76). %).

    (3e) (3S) -6-[((3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl) (4-nitrobenzene-1-sulfonyl) amino ] -7-{[tertiary-butyl (dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tertiary-butyl 3-methyl Ester    

Under nitrogen, under ice-cooling, in (R) -5,5-diphenyl-2-methyl-3,4-propanol-1,3,2-oxaboridine (645mg, 2.33mmol) To a solution of tetrahydrofuran (58 mL), borane dimethyl sulfide (2.21 mL, 23.3 mmol) was added and stirred for 10 minutes. Next, (3S) -6-[{3- [4- (benzyloxy) phenyl] -3-sideoxypropyl} (4-nitro) obtained in Reference Example 3 (3d) was slowly added dropwise. Benzene-1-sulfonyl) amino] -7-{[tertiary butyl (dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -di A solution of 2-tert-butyl 3-methyl formate (10.0 g, 11.6 mmol) in tetrahydrofuran (58 mL) was stirred under ice-cooling for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 89: 11-68: 32) to obtain the title compound (9.42 g, yield 94%) as a pale yellow amorphous substance.

    (3f) (3S) -6-[((3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl) (4-nitrobenzene-1-sulfonyl) amino ] -7-Hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6-[{(3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl} (4-nitrobenzene-1) obtained in Reference Example 3 (3e) -Sulfofluorenyl) amino] -7-{[tertiary butyl (dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2- To a solution of tertiary butyl 3-methyl ester (152 g, 134 mmol) in tetrahydrofuran (1350 mL), add acetic acid (9.23 mL, 161 mmol) and tetrabutylammonium fluoride (1.0 M-tetrahydrofuran solution, 161 mL) under ice cooling. 161 mmol), and stirred at the same temperature for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction solution, and extracted with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 2: 1-1: 1-1). : 2) After purification, the residue obtained by concentration under reduced pressure was washed with diethyl ether to obtain 85.6 g of the title compound as a pale yellow solid (yield: 85%).

    (3g) (4R, 9S) -4- [4- (benzyloxy) phenyl] -1- (4-nitrobenzene-1-sulfonyl) -1,3,4,7,9,10 -Hexahydro [1,4] oxacridine [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl 9-methyl ester    

(3S) -6-[{(3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl} (4-nitrate) obtained in Reference Example 3 (3f) under a nitrogen atmosphere Phenyl-1-sulfonyl) amino] -7-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (3.06g , 4.09 mmol) in a tetrahydrofuran (10 mL) / toluene (20 mL) solution, and tri-n-butylphosphine (2.04 mL, 8.18 mmol) and 1,1'-azobis (N, N-dimethyl) were sequentially added. Formamidine) (1.06 g, 6.14 mmol), heated to 45 ° C, and stirred for 0.5 hours. Water was added to the reaction solution, and extracted with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20-60: 40) to obtain the title compound (2.23 g, yield 75%) as a pale yellow amorphous substance.

    (3h) (4R, 9S) -4- [4- (benzyloxy) phenyl] -1,3,4,7,9,10-hexahydro [1,4] oxyazepine [3,2 -g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl 9-methyl ester    

(4R, 9S) -4- [4- (benzyloxy) phenyl] -1- (4-nitrobenzene-1-sulfonyl)-obtained in Reference Example 3 (3g) under a nitrogen atmosphere 1,3,4,7,9,10-hexahydro [1,4] oxacridine [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl 9 -Methyl ester (2.22g, 3.04mmol) in N, N-dimethylformamide (30.4mL), 4-mercaptobenzoic acid (1.41g, 9.13mmol) and potassium carbonate (1.68g) were added sequentially. , 12.2 mmol), and stirred at room temperature for 2 hours, then heated to 45 ° C. and stirred for 3 hours. The reaction solution was diluted with ethyl acetate, and insoluble matters were filtered off. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25-50: 50, and then dichloromethane: methanol = 90: 10) to obtain 1.11 g of the title compound as a white solid (yield: 67%).

    (3i) (4R, 9S) -4- [4- (benzyloxy) phenyl] -1-methyl-1,3,4,7,9,10-hexahydro [1,4] oxazepine幷 [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl 9-methyl ester    

(4R, 9S) -4- [4- (benzyloxy) phenyl] -1,3,4,7,9,10-hexahydro [1 , 4] oxacridine [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl 9-methyl ester (14.0 g, 25.7 mmol) in dichloromethane ( 257 mL) solution, under ice-cooling, sequentially add an aqueous formaldehyde solution (37 wt%, 37.9 mL, 514 mmol) and sodium triacetoxyborohydride (21.78 g, 102.7 mmol), and stir at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 13.8 g of the title compound as a pale yellow amorphous substance (yield 96%).

    (3j) (4R, 9S) -4- [4- (benzyloxy) phenyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4 ] Oxyacryl [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -4- [4- (benzyloxy) phenyl] -1-methyl-1,3,4,7,9,10 obtained in Reference Example 3 (3i) under a nitrogen atmosphere -Hexahydro [1,4] oxacridine [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl 9-methyl ester (1.97 g, 3.53 mmol) To a solution of dichloromethane (35.3 mL), under ice cooling, trimethylsilane iodide (1.21 mL, 8.82 mmol) was added and stirred for 15 minutes. The reaction solution was diluted with dichloromethane, and a saturated aqueous sodium bicarbonate solution was added to separate the organic layer. The aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (amine group; n-hexane: ethyl acetate = 65: 35-40: 60) to obtain 1.31 g of the title compound as a white solid (yield: 81%).

    (3k) (4R, 9S) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine幷 [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -4- [4- (benzyloxy) phenyl] -1-methyl-1,3,4,7,9,10-octahydro [obtained in Reference Example 3 (3j) [ In a mixed suspension of 1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (1.31 g, 2.86 mmol) in ethyl acetate (9.5 mL) / methanol (9.5 mL), 10% palladium-carbon catalyst (wet, 50 wt%, 610 mg, 0.571 mmol) was added, and stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in ethyl acetate / diethyl ether, and filtered to obtain 1.01 g of the title compound as a white solid (yield: 96). %).

(4R, 9S) -4- [4- (benzyloxy) phenyl] -1-methyl-1,2,3,4,7,8,9,10- obtained in Reference Example 3 (3i) Octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester can also be synthesized as follows.

    (3l) (3S) -6-((3- [4- (benzyloxy) phenyl] -3-sideoxypropyl} amino) -7-{[tertiary butyl (dimethyl) Silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6-amino-7-{[tertiary butyl (dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2 obtained in Reference Example 3 (3b) , 3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (2.6 g, 8.3 mmmol) in ethanol (100 mL) suspension, and sequentially added according to Angewandte Chemie-International Edition, 2011, 50, 12335 -12338 described 1- [4- (benzyloxy) phenyl] -2-propen-1-one (4.0 g, 8.3 mmol) and trimethylamine (0.74 mL, 5.4 mmol), Stir for 3 hours. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 4.07 g of the title compound (quantitative) as a yellow amorphous substance.

    (3m) (3S) -6-[{3- [4- (benzyloxy) phenyl] -3-oxopropyl} (methyl) amino] -7-{[tertiary butyl ( Dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6-({3- [4- (benzyloxy) phenyl] -3-oxopropylpropyl} amino) -7-{[tertiary Butyl (dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester, as in Reference Example 3 ( The method described in 3i) was reacted in the same manner to obtain the title compound (yield 73%) as a pale yellow amorphous substance.

    (3n) (3S) -6-[{(3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl} (methyl) amino] -7-{[tertiary butane (Dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6-[{3- [4- (benzyloxy) phenyl] -3-sideoxypropyl} (methyl) amino] -7- obtained in Reference Example 3 (3m) was used {[Tertiary butyl (dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester, and The reaction was performed in the same manner as described in Reference Example 3 (3e) to obtain the title compound as a colorless amorphous substance (yield: 90%).

    (3o) (3S) -6-[[((3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl) (methyl) amino] -7-hydroxy-3,4 -Dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6-[{(3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl} (methyl) amino]-obtained in Reference Example 3 (3n) was used 7-{[tertiary-butyl (dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tertiary-butyl 3-methyl ester The reaction was carried out in the same manner as in the method described in Reference Example 3 (3f) to obtain the title compound as a colorless amorphous substance (yield: 94%).

    (3i) (4R, 9S) -4- [4- (benzyloxy) phenyl] -1-methyl-1,3,4,7,9,10-hexahydro [1,4] oxazepine幷 [3,2-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-tert-butyl 9-methyl ester    

(3S) -6-[{(3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl} (methyl) amino]-obtained in Reference Example 3 (3o) In a solution of 7-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (1.92 g, 3.33 mmol) in toluene (40 mL), Triphenylphosphine (1.22g, 4.66mmmol) and diethylazodicarboxylate (2.2M-toluene solution, 2.0mL, 4.33mmol) were added sequentially, and the mixture was stirred at room temperature for 30 minutes. Saturated saline was added to the reaction solution, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain 590 mg of the title compound as a colorless solid (yield: 32%).

    Reference example 4    

(1S) -1- (3,4-dichlorophenyl) propane-1-ol

Under nitrogen, under ice cooling, at (R) -5,5-diphenyl-2-methyl-3,4-propanol-1,3,2-oxaboridine (1.6 g, 5.9 mmol) To a solution of tetrahydrofuran (60 mL) was added borane dimethyl sulfide (5.6 mL, 59 mmol), and stirred for 5 minutes. Next, a solution of 1- (3,4-dichlorophenyl) propane-1-one (6.0 g, 29.5 mmol) in tetrahydrofuran (40 mL) was slowly added dropwise under ice-cooling, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and after the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain 6.3 g of the title compound (quantitative) as a colorless oily substance.

    Reference example 5    

(1R) -1- (3,4-dichlorophenyl) propane-1-ol

Using (S) -5,5-diphenyl-2-methyl-3,4-propanol-1,3,2-oxaboridine, the reaction was performed in the same manner as described in Reference Example 4 to obtain The title compound as a colorless oily substance (99% yield).

    Reference example 6    

(1S) -1- (3,4-difluorophenyl) propane-1-ol

Using 1- (3,4-difluorophenyl) propane-1-one, a reaction was carried out in the same manner as described in Reference Example 4 to obtain the title compound (quantitative) as a colorless oily substance.

    Reference example 7    

1- (3,4-dichlorophenyl) -2-methoxyethanol

    (7a) 3,4-Dichloro-N-methoxy-N-methylbenzamide    

To a solution of 3,4-dichlorobenzoic acid (10 g, 52.4 mmol) and N, O-dimethylhydroxylamine hydrochloride (5.62 g, 57.6 mmol) in dichloromethane (300 mL) under a nitrogen atmosphere, add Triethylamine (9.43mL, 68.1mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (15.1g, 78.5mmol), and stirred at room temperature 16 hours. Water was added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25) to obtain 11.1 g of the title compound as a colorless oily substance (yield 91%).

    (7b) 1- (3,4-dichlorophenyl) -2-methoxyethyl ketone    

Under a nitrogen atmosphere, a solution of tributyl (methoxymethyl) tin (660mg, 1.97mmol) in tetrahydrofuran (5mL) was cooled to -78 ° C, and n-butyllithium (1.6M-n-hexane solution) (2mL, 1.97 mmol) and stirred at -78 ° C for 10 minutes. Next, a tetrahydrofuran solution (3 mL) of 3,4-dichloro-N-methoxy-N-methylbenzamide (200 mg, 0.954 mmol) obtained in Reference Example 7 (7a) was added dropwise at -78. Stir at 0.5 ° C for 0.5 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and after warming to room temperature, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-75: 25) to obtain 71 mg of the title compound as a colorless oily substance (yield 38%).

    (7c) 1- (3,4-dichlorophenyl) -2-methoxyethanol    

Under a nitrogen atmosphere, in a solution of 1- (3,4-dichlorophenyl) -2-methoxyethyl ketone (31 mg, 0.142 mmol) in methanol (1 mL) obtained in Reference Example 7 (7b), Then, after adding sodium borohydride (16 mg, 0.425 mmol), the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water was added, and extraction was performed twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40) to obtain 31 mg of the title compound (quantitative) as a colorless oily substance.

    Reference example 8    

(3,4-dichlorophenyl) (phenyl) methanol

    (8a) (3,4-dichlorophenyl) (phenyl) methanone    

The 3,4-dichloro-N-methoxy-N-methylbenzamide obtained in Reference Example 7 (7a) was used and phenylmagnesium bromide (1M-tetrahydrofuran solution) was used in place of tributyl A combination of (methoxymethyl) tin and n-butyllithium was reacted in the same manner as in the method described in Reference Example 7 (7b) to obtain the title compound (quantitative) as a white solid.

    (8b) (3,4-dichlorophenyl) (phenyl) methanol    

Using (3,4-dichlorophenyl) (phenyl) methanone obtained in Reference Example 8 (8a), the reaction was carried out in the same manner as described in Reference Example 7 (7c) to obtain the title of a colorless oily substance. Compound (89% yield).

    Reference example 9    

5,6-dichloro-2,3-dihydro-1H-inden-1-ol

Using 4,5-dichloro-2,3-dihydro-1H-inden-1-one, the reaction was carried out in the same manner as described in Reference Example 7 (7c) to obtain the title compound as a pale brown solid (yield 86) %).

    Reference example 10    

Cyclopropyl (3,4-dichlorophenyl) methanol

    (10a) cyclopropyl (3,4-dichlorophenyl) methanone    

The 3,4-dichloro-N-methoxy-N-methylbenzamide obtained in Reference Example 7 (7a) was used, and cyclopropylmagnesium bromide (1M-tetrahydrofuran solution) was used instead of tributyl A combination of methyl (methoxymethyl) tin and n-butyllithium was reacted in the same manner as in the method described in Reference Example 7 (7b) to obtain the title compound as a colorless oily substance (yield: 81%).

    (10b) cyclopropyl (3,4-dichlorophenyl) methanol    

Using the cyclopropyl (3,4-dichlorophenyl) methanone obtained in Reference Example 10 (10a), the same reaction as in the method described in Reference Example 7 (7c) was performed to obtain the title compound as a colorless oily substance. (97% yield).

    Reference example 11    

(1S) -1- (5-chloropyridin-3-yl) propane-1-ol

    (11a) 5-chloro-N-methoxy-N-methylpyridine-3-carboxamide    

To a solution of 5-chloropyridine-3-carboxylic acid (2.5 g, 16 mmol) in N, N-dimethylformamidine (53 mL) under a nitrogen atmosphere, N, O-dimethylhydroxylamine hydrochloride ( 1.9 g, 19 mmol), 1-hydroxybenzotriazole (1.1 g, 7.9 mmol) and N, N-diisopropylethylamine (4.1 mL, 24 mmol) and stirred. Next, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.7 g, 19 mmol) was added and stirred at 50 ° C for 3 hours. After the reaction solution was allowed to cool to room temperature, water was added to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-70: 30) to obtain 2.96 g of the title compound as a colorless oily substance (yield: 93%).

    (11b) 1- (5-chloropyridin-3-yl) propane-1-one    

The 5-chloro-N-methoxy-N-methylpyridine-3-carboxamide obtained in Reference Example 11 (11a) was used, and ethyl magnesium bromide (1M-tetrahydrofuran solution) was used in place of tributyl A combination of (methoxymethyl) tin and n-butyllithium was reacted in the same manner as in the method described in Reference Example 7 (7b) to obtain the title compound (yield: 35%) as a colorless oily substance.

    (11c) (1S) -1- (5-chloropyridin-3-yl) propane-1-ol    

Using 1- (5-chloropyridin-3-yl) propane-1-one obtained in Reference Example 11 (11b), the reaction was carried out in the same manner as in the method described in Reference Example 4 to obtain the title compound as a colorless oily substance ( Yield: 49%).

    Reference example 12    

(1S) -1- (5,6-dichloropyridin-3-yl) propane-1-ol

    (12a) 5,6-Dichloro-N-methoxy-N-methylpyridine-3-carboxamide    

Using 5.6-dichloropyridine-3-carboxylic acid, the reaction was carried out in the same manner as described in Reference Example 11 (11a) to obtain the title compound as a white solid (yield 64%).

    (12b) 1- (5,6-dichloropyridin-3-yl) propane-1-one    

The 5,6-dichloro-N-methoxy-N-methylpyridine-3-carboxamide obtained in Reference Example 12 (12a) was used, and ethyl magnesium bromide (1M-tetrahydrofuran solution) was used instead. A combination of tributyl (methoxymethyl) tin and n-butyllithium was reacted in the same manner as in the method described in Reference Example 7 (7b) to obtain the title compound as a white solid (yield: 57%).

    (12c) (1S) -1- (5,6-dichloropyridin-3-yl) propane-1-ol    

Using 1- (5,6-dichloropyridin-3-yl) propane-1-one obtained in Reference Example 12 (12b), the reaction was performed in the same manner as described in Reference Example 4 to obtain the title compound as a white solid. (92% yield).

    Reference example 13    

(2S, 8S) -2- (4-hydroxyphenyl) -4-methyl-3,4,5,7,8,10-hexahydro [1,4] oxyazepine [6,7-g ] Isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl 8-methyl ester

    (13a) N- (tertiary butoxycarbonyl) -3-iodo-L-tyrosine methyl ester    

In a solution of N- (tertiary butoxycarbonyl) -L-tyrosine methyl ester (68 g, 0.23 mol) in ethanol (1000 mL), 2N-sulfuric acid (115 mL, 0.115 mol) was added under ice cooling. A solution of 1,3-diiodo-5,5-dimethylhydantoin (45.5 g, 0.12 mol) in ethanol (300 mL) was added dropwise over 30 minutes, and the temperature was gradually raised from 0 ° C to 10 ° C and stirred for 3 hours. . A 2N-sodium hydroxide aqueous solution was added to adjust the pH to 7-8, and a 10% sodium bisulfite aqueous solution (20 mL) was added, followed by stirring at room temperature for 10 minutes. The ethanol in the reaction solution was distilled off under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 106 g of the title compound (purity 75%, yield 82%) as a colorless amorphous substance. mixture.

    (13b) O-Benzyl-N- (tertiary butoxycarbonyl) -3-iodo-L-tyrosine methyl ester    

In a solution of N- (tertiary butoxycarbonyl) -3-iodo-L-tyrosine methyl ester (106 g, purity 75%, 0.19 mol) in acetone (800 mL) obtained in Reference Example 13 (13a), Potassium carbonate (47 g, 0.34 mol) and benzyl bromide (34 mL, 0.28 mol) were added at room temperature, heated to 60 ° C, and stirred for 6 hours. The reaction solution was left to cool to room temperature, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain 81 g of the title compound as a colorless solid (yield 84%).

    (13c) O-benzyl-N- (tertiary butoxycarbonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2- ) -L-tyrosine methyl ester    

O-benzyl-N- (tertiary butoxycarbonyl) -3-iodo-L-tyrosine methyl ester (43 g, 84 mmol), biboric acid frequency obtained in Reference Example 13 (13b) under a nitrogen atmosphere In a mixed solution of bis (pinacolato) diboron (42 g, 168 mmol) and potassium acetate (33 g, 0.21 mol) in N, N-dimethylformamide (500 mL), [1,1'-bis (Diphenylphosphine) ferrocene] palladium (II) dichloride (3.4 g, 4.2 mmol) was stirred at 80 ° C for 8 hours. The reaction solution was left to cool to room temperature, diluted with ethyl acetate and water, and the insoluble matter was filtered off. The organic layer was washed three times with saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 43 g of the title compound (quantitative) as a pale yellow amorphous substance.

    (13d) O-benzyl-N- (tertiary butoxycarbonyl) -3-hydroxy-L-tyrosine methyl ester    

O-benzyl-N- (tertiary butoxycarbonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxane obtained in Reference Example 13 (13c) Cyclopentyl-2-yl) -L-tyrosine methyl ester (38 g, 75 mmol) in methanol (400 mL) was added dropwise with hydrogen peroxide water (30 w%, 21 mL) under ice cooling, and the temperature was raised to Stir at room temperature for 16 hours. The reaction solution was ice-cooled, and a 20% aqueous sodium hydrogen sulfite solution (150 mL) was slowly added, followed by stirring at the same temperature for 30 minutes. Water (300 mL) was added, and after dilution, methanol in the reaction solution was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 30 g of the title compound (quantitative) as a colorless amorphous substance.

    (13e) (3S) -7- (benzyloxy) -6-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

O-benzyl-N- (tertiary butoxycarbonyl) -3-hydroxy-L-tyrosine methyl ester (56 g, 0.14 mol) in dichloromethane (300 mL) obtained in Reference Example 13 (13d) To the solution, trifluoroacetic acid (70 mL, 0.9 mol) was added and stirred at room temperature for 1 hour. The reaction solution was heated to 35 ° C and stirred for 1 hour. The reaction solution was left to cool to room temperature, dichloromethane (500 mL) and paraformaldehyde (12.6 g, 0.42 mol) were added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and trifluoroacetic acid was removed by azeotropy using ethyl acetate. The obtained residue was suspended in ethyl acetate (300 mL) and water (200 mL), and sodium bicarbonate (58 g, 0.70 mol) was gradually added and neutralized. Next, di-tertiary butyl dicarbonate (38 mL, 0.17 mol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain 44 g of the title compound (yield 76%) as a pale yellow amorphous substance.

    (13f) (3S) -7- (benzyloxy) -6-[(trifluoromethanesulfonyl) oxy] -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2 -Tertiary butyl 3-methyl ester    

(3S) -7- (benzyloxy) -6-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl obtained in Reference Example 13 (13e) To a solution of methyl 3-methyl ester (44 g, 106 mmol) and pyridine (13 mL, 160 mmol) in dichloromethane (400 mL), add trifluoromethanesulfonic anhydride (20 mL, 117 mmol) under ice cooling, and stir at room temperature for 1 hour. Saturated sodium bicarbonate water was added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes, and then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 55 g (yield 95%) of the title compound as a pale yellow amorphous substance.

    (13g) (3S) -7- (benzyloxy) -6-vinyl-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -7- (benzyloxy) -6-[(trifluoromethanesulfonyl) oxy] -3,4-dihydroisoquinoline-2,3 obtained in Reference Example 13 (13f) (1H) -Dicarboxylic acid 2-tertiary-butyl 3-methyl ester (45 g, 82 mmol) (400 mL) solution, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxolane (20 mL, 118 mmol), potassium carbonate (35 g, 250 mmol) were added ) And water (150 mL), and then (triphenylphosphine) palladium (0) (5.0 g, 4.4 mmol) was added, and stirred at 80 ° C. for 6 hours under a nitrogen atmosphere. The reaction solution was left to cool to room temperature, and the solvent was distilled off under reduced pressure. To the residue was added saturated brine, which was extracted with ethyl acetate, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 27 g of the title compound (yield 76%) as a pale yellow amorphous substance.

    (13h) (3S) -7- (benzyloxy) -6-methylamino-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl Ester    

(3S) -7- (benzyloxy) -6-vinyl-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tertiary obtained in Reference Example 13 (13g) To a solution of butyl 3-methyl ester (27 g, 64 mmol) in tetrahydrofuran (300 mL), potassium osmium (IV) acid dihydrate (1.17 g, 3.19 mmol) was added, and then sodium periodate (27 g) was added under ice-cooling. , 0.13 mol) in water (300 mL), and stirred for 5 minutes. After further adding 2,6-lutidine (7.5 mL, 63 mmol) under ice cooling, the temperature was raised to room temperature and stirred for 1 hour. Again, the reaction solution was ice-cooled, and a 20% sodium bisulfite aqueous solution (400 mL) was slowly added, followed by stirring at the same temperature for 10 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain 21.9 g of the title compound as a brown amorphous substance (yield: 81%).

    (13i) (3S) -6-methylamino-7-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -7- (benzyloxy) -6-methylamino-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tris obtained in Reference Example 13 (13h) To a solution of butyl 3-methyl ester (4.0 g, 9.4 mmol) in ethyl acetate (63 mL) / ethanol (31 mL), 10% palladium on carbon (wet, 50 wt%, 600 mg) was added. Stir at room temperature for 3 hours. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure to obtain 3.15 g of the title compound (quantitative) as a colorless oily substance.

    (13j) (3S) -6-methylamino-7-{[tris (propane-2-yl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -di 2-tert-butyl 3-methyl formate    

(3S) -6-methylamino-7-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3 obtained in Reference Example 13 (13i) -Methyl ester (15.5g, 46.2mmol) in a solution of N, N-dimethylformamidine (116mL), imidazole (4.09g, 60.1mmol) and triisopropylchlorosilane (12.7mL, 60.1mmol) ) And stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate / n-hexane, and then washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 19: 1-9: 1) to obtain 22.7 g of the title compound (quantitative) as a colorless oily substance.

    (13k) (3S) -6-{[(2-nitrobenzene-1-sulfonyl) amino] methyl} -7-{[tris (propane-2-yl) silyl] oxy}- 3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6-methylamino-7-{[tris (propane-2-yl) silyl] oxy} -3,4-dihydroiso, obtained in Reference Example 13 (13j) under a nitrogen atmosphere To a solution of quinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (20.0g, 40.7mmol) in ethanol (136mL), hydroxylamine hydrochloride (3.67g) was added at room temperature. , 52.9 mmol) and sodium acetate (5.01 g, 61.0 mmol), and stirred at room temperature for 2 hours. After the reaction solution was diluted with ethyl acetate / n-hexane (1: 1 mixed solution), water was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oxime intermediate as a colorless oily substance. The acetic acid (102 mL) solution of the obtained oxime intermediate was heated to 40 ° C., and finely pulverized zinc powder (16.0 g, 244 mmol) was added in 4 portions over 10 minutes, and then heated at 40 ° C. for 20 minutes. The reaction solution was diluted with ethyl acetate and poured into an ice-cold ammonia solution. After the insoluble matter was filtered off, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a primary amine intermediate as a pale yellow oily substance. Next, in a dichloromethane (203 mL) solution of the obtained primary amine intermediate under a nitrogen atmosphere, triethylamine (7.89 mL, 56.9 mmol) and 2-nitrobenzenesulfonyl chloride (12.6 g, 56.9 mmol), and stirred at room temperature for 2 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5-75: 25) to obtain 21.5 g of the title compound as a pale yellow amorphous substance (yield: 78%).

    (13l) (3S) -6-{[(2-nitrobenzene-1-sulfonyl) (2- {4-[(2-nitrobenzene-1-sulfonyl) oxy] phenyl) -2-Phenoxyethyl) amino] methyl} -7-{[tris (propane-2-yl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H ) -Dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6-{[(2-nitrobenzene-1-sulfonyl) amino] methyl} -7-{[tri (propane- 2-yl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (21.5 g, 21.7 mmol) and reference N-N-dimethylformamidine of 4- (bromoethylfluorenyl) phenyl 2-nitrobenzene-1-sulfonic acid ester (purity 80%, 19.0 g, 38.1 mmol) obtained in Example 13 (13r) To the amine (160 mL) solution, potassium carbonate (6.36 g, 46.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-60: 40) to obtain 28.6 g of the title compound as a yellow amorphous substance (yield 90%).

    (13m) (3S) -6-(([((2R) -2-hydroxy-2- {4-[(2-nitrobenzene-1-sulfonyl) oxy] phenyl) ethyl) (2 -Nitrobenzene-1-sulfonyl) amino} methyl) -7-{[tris (propane-2-yl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -Dicarboxylic acid 2-tert-butyl 3-methyl ester    

Tetrahydrofuran (170mL) at (R) -5,5-diphenyl-2-methyl-3,4-propanol-1,3,2-oxaboridine (2.27g, 16.7mmol) under nitrogen atmosphere ) In the solution, borane dimethyl sulfide (15.9 mL, 167 mmol) was added dropwise under ice cooling, and the solution was directly stirred under ice cooling for 10 minutes. Next, the 2- (3S) -6-{[(2-nitrobenzene-1-sulfonyl) (2- {4-[(2-nitrobenzene-1) -Sulfofluorenyl) oxy] phenyl} -2-oxoethyl) amino] methyl} -7-{[tris (propane-2-yl) silyl] oxy} -3,4- A solution of dihydroisoquinoline-2,3 (1H) -dicarboxylic acid tert-butyl 3-methyl ester (83.5 g, 83.7 mmol) in tetrahydrofuran (170 mL) was cooled on ice, and then slowly added dropwise to the reaction solution to raise the temperature Stir to room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 0-2: 1-1: 1-1: 2) to obtain 81.2 g of the title compound as a pale yellow amorphous substance (yield: 97%).

    (13n) (3S) -7-hydroxy-6-((((2R) -2-hydroxy-2- {4-[(2-nitrobenzene-1-sulfonyl) oxy) phenyl) ethyl Group) (2-nitrobenzene-1-sulfonyl) amino} methyl) -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl Ester    

(3S) -6-({[((2R) -2-hydroxy-2- {4-[(2-nitrobenzene-1-sulfonyl)) obtained in Reference Example 13 (13m) under a nitrogen atmosphere Oxy] phenyl} ethyl] (2-nitrobenzene-1-sulfonyl) amino} methyl) -7-{[tris (propane-2-yl) silyl] oxy} -3, In a solution of 4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (81.2 g, 81.3 mmol) in tetrahydrofuran (542 mL), acetic acid was added dropwise under ice cooling. (6.51 mL, 114 mmol) and tetrabutylammonium fluoride (1M-tetrahydrofuran solution, 110 mL, 114 mmol), stirred directly under ice-cooling for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 0-2: 1-1: 1-1: 2) to obtain 43.2 g of the title compound as a pale yellow amorphous substance (yield: 63%).

    (13o) (2S, 8S) -4- (2-nitrobenzene-1-sulfonyl) -2- {4-[(2-nitrobenzene-1-sulfonyl) oxy] phenyl} -3,4,5,7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl 8-methyl ester    

(3S) -7-hydroxy-6-({[((2R) -2-hydroxy-2- {4-[(2-nitrobenzene-1- Sulfonyl) oxy] phenyl} ethyl] (2-nitrobenzene-1-sulfonyl) amino} methyl) -3,4-dihydroisoquinoline-2,3 (1H)- To a solution of 2-tert-butyl 3-methyl dicarboxylate (43.2 g, 51.3 mmol) in toluene (510 mL) / tetrahydrofuran (103 mL), tri-n-butylphosphine (19.2 mL, 76.9 mmol) and 1,1'-Azobis (N, N-dimethylformamide) (13.2 g, 76.9 mmol), and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25-50: 50) to obtain 36.4 g of the title compound as a pale yellow amorphous substance (yield 86%).

    (13p) (2S, 8S) -2- (4-hydroxyphenyl) -3,4,5,7,8,10-hexahydro [1,4] oxazepine [6,7-g] iso Quinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl 8-methyl ester    

(2S, 8S) -4- (2-nitrobenzene-1-sulfonyl) -2- {4-[(2-nitrobenzene-1) obtained in Reference Example 13 (13o) under a nitrogen atmosphere -Sulfofluorenyl) oxy] phenyl} -3,4,5,7,8,10-hexahydro [1,4] oxazepine [6,7-g] isoquinoline-8,9 ( 2H) -Dicarboxylic acid 9-tertiary-butyl 8-methyl ester (36.4 g, 44.1 mmol) in N, N-dimethylformamide (441 mL) solution, and potassium carbonate (36.6 g, 265 mmol) were sequentially added. ) And 4-mercaptobenzoic acid (27.2 g, 177 mmol), and stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, insoluble matters were filtered off, water was added to the filtrate to separate the organic layer, and the aqueous layer was extracted 4 times with ethyl acetate. The organic layers were combined, washed once with saturated sodium bicarbonate, washed four times with water, once with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 0-85: 15) to obtain 27.9 g of the title compound (quantitative) as a pale yellow oily substance.

    (13q) (2S, 8S) -2- (4-hydroxyphenyl) -4-methyl-3,4,5,7,8,10-hexahydro [1,4] oxyazepine [6, 7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl 8-methyl ester    

(2S, 8S) -2- (4-hydroxyphenyl) -3,4,5,7,8,10-hexahydro [1,4] oxyazepine [13] obtained in Reference Example 13 (13p) [ 6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl 8-methyl ester (27.9g, 46.7mmol) in dichloromethane (311mL) was added sequentially Aqueous formaldehyde (37%, 10 mL, 140 mmol) and sodium triacetoxyborohydride (29.7 g, 140 mmol) were stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 0-95: 5) to obtain 12.3 g of the title compound as a pale yellow amorphous substance (yield 56%).

    (13r) 4- (Bromoethylfluorenyl) phenyl 2-nitrobenzene-1-sulfonate    

Under a nitrogen atmosphere, in a solution of 2-bromo-4'-hydroxyacetophenone (25.0g, 116mmol) in tetrahydrofuran (465mL) / n-hexane (116mL), add triethylamine (17.7mL, 128mmol) under ice cooling ) And 2-nitrobenzenesulfonyl chloride (27.1 g, 122 mmol), and stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90 / 10-60 / 40) to obtain 44.0 g of the title compound (purity 80%, yield 76%) as a white solid.

    Reference example 14    

(1R) -1- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2- (methylamino) ethanol

    (14a) 2,2,2-trifluoro-N- [2- (4-hydroxyphenyl) -2-oxoethyl] -N-methylacetamide    

Methylamine solution (2.0M-tetrahydrofuran solution, 21mL, 42mmol) was diluted with tetrahydrofuran (30mL), and 2-bromo-1- (4-hydroxyphenyl) ethanone (3g, 14mmol) was added dropwise under ice cooling. After the solution in tetrahydrofuran (20 mL) was stirred directly at the same temperature for 20 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was suspended in tetrahydrofuran (40 mL). Under ice cooling, triethylamine (5.8 mL, 42 mmol) and trifluoroacetic anhydride (2.9 mL, 21 mmol) were added, and the mixture was directly stirred at the same temperature. 30 minutes. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain 1.4 g of the title compound as a colorless solid (yield: 38%).

    (14b) N- (2- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -2-oxoethyl) -2,2,2 -Trifluoro-N-methylacetamide    

2,2,2-trifluoro-N- [2- (4-hydroxyphenyl) -2-oxoethyl] -N-methylacetamide (800 mg) obtained in Reference Example 14 (14a) , 3.06 mmol) and (1S) -1- (3,4-dichlorophenyl) -1-propanol (820 mg, 3.98 mmol) in toluene (15 mL) obtained in Reference Example 4 under ice cooling, After adding 1,1'-azobis (N, N-dimethylformamide) (791 mg, 4.60 mmol) and tri-n-butylphosphine (1.14 mL, 4.60 mmol), the mixture was stirred at 40 ° C for 1 hour. After the reaction solution was allowed to cool to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 1.4 g of the title compound (quantitative) as a colorless amorphous substance.

    (14c) N-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2-hydroxyethyl] -2,2 , 2-trifluoro-N-methylacetamide    

Using N- (2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2- pendant ethoxyethyl obtained in Reference Example 14 (14b) ) -2,2,2-trifluoro-N-methylacetamide was reacted in the same manner as described in Reference Example 13 (13m) to obtain the title compound as a colorless amorphous substance (yield 67%) ).

    (14d) (1R) -1- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2- (methylamino) ethanol    

The N-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2-hydroxy group obtained in Reference Example 14 (14c) Ethyl] -2,2,2-trifluoro-N-methylacetamide (940 mg, 2.09 mmol) was dissolved in a 90% methanol aqueous solution (20 mL), potassium carbonate (940 mg) was added, and the mixture was stirred at 50 ° C for 1 hour. The reaction solution was left to cool to room temperature, and insoluble matters were filtered off, and then the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 806 mg of the title compound (quantitative) as a colorless amorphous substance.

    Reference example 15    

(S)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methanol

    (15a) (3,4-dichlorophenyl) (tetrahydropyran-4-yl) methanol    

In a solution of 4-methylfluorenyltetrahydropyran (2.98 g, 26.1 mmol) in tetrahydrofuran (65 mL), under ice cooling, zinc chloride (1.0 M-diethyl ether solution, 1.3 mL, 1.3 mmol) was sequentially added. ) And 3,4-dichlorophenylmagnesium bromide (0.5M-tetrahydrofuran solution, 57 mL, 28.7 mmol), and stirred directly at the same temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with a 10% citric acid aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 19: 1 ~ 2: 1) to obtain 3.31 g of the title compound as a colorless solid (yield: 49%).

    (15b) 1-tert-butyl 2-[(S)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methyl] (2S) -pyrrolidine-1,2- Diformate    

(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methanol (3.31 g, 12.7 mmol), 1-tertiary butoxycarbonyl-L- obtained in Reference Example 15 (15a) In a solution of proline (3.27 g, 15.2 mmol) and 4-dimethylaminopyridine (1.55 g, 12.7 mmol) in dichloromethane (63 mL), 1- (3-dimethylamine was added under ice cooling. After propylpropyl) -3-ethylcarbodiimide hydrochloride (3.16 g, 16.5 mmol), the temperature was raised to room temperature and stirred for 7 hours. It was diluted with dichloromethane, and the organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1-2: 1) to separate non-mirror isomers to obtain 2.04 g of the title compound as a colorless oily substance (yield 35%).

    (15c) (S)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methanol    

1-tert-butyl 2-[(S)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methyl] (2S)-obtained in Reference Example 15 (15b) To a solution of pyrrolidine-1,2-dicarboxylate (2.04 g, 4.45 mmol) in tetrahydrofuran (30 mL) / methanol (15 mL), a 1N-sodium hydroxide aqueous solution (8.9 mL, 8.9 mmol) was added, and the mixture was stirred at room temperature. 3 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1-3: 1). Recrystallization was performed using a mixed solvent of chloroform, 2-propanol, and diisopropyl ether to obtain 437 mg of the title compound as a colorless solid (yield: 38%).

    Reference Example 16    

(9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

    (16a) methyl N- (tertiary butoxycarbonyl) -3-iodo-O- (methoxymethyl) -L-tyrosine    

To a solution of N- (tertiary butoxycarbonyl) -3-iodo-L-tyrosinecarboxylic acid (12.14 g, 28.82 mmol) in dichloromethane (120 mL) obtained in Reference Example 13 (13a), N was added, N-diisopropylethylamine (10.0 mL, 57.64 mmol) and chloromethyl methyl ether (2.60 mL, 34.58 mmol), and stirred at room temperature for 30 minutes. Next, methanol (0.58 mL, 14.41 mmol) was added to the reaction solution, and after stirring at room temperature for 20 minutes, the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 → 60/40) to obtain 11.46 g of the title compound as a colorless oily substance (yield: 85%).

    (16b) methyl N- (tertiary butoxycarbonyl) -O- (methoxymethyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentyl-2-yl) -L-tyrosine    

Of methyl N- (tertiary butoxycarbonyl) -3-iodo-O- (methoxymethyl) -L-tyrosine (11.46 g, 24.63 mmol) obtained in Reference Example 16 (16a) To a solution of dimethyl sulfene (200 mL), 4,4,5,5-octamethyl-2,2-bis-1,3,2-dioxolane (12.51 g, 49.26 mmol) was added. [1,1'-bis (diphenylphosphine) ferrocene] palladium (II) dichloromethane adduct (1.01 g, 1.23 mmol), and stirred at room temperature for 5 minutes. Next, potassium acetate (9.97 g, 98.52 mmol) was added, and it stirred at 80 degreeC for 22 hours. After the reaction solution was cooled to room temperature, saturated brine (50 mL) and water (50 mL) were added and stirred for 10 minutes. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate was separated, and the aqueous layer was extracted with ethyl acetate (200 mL). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 → 60/40) to obtain 11.46 g of the title compound as a pale yellow oily substance (yield 74%).

    (16c) methyl N- (tertiary butoxycarbonyl) -3-hydroxy-O- (methoxymethyl) -L-tyrosine    

Methyl N- (tertiary butoxycarbonyl) -O- (methoxymethyl) -3- (4,4,5,5-tetramethyl-1, obtained in Reference Example 16 (16b), In a solution of 3,2-dioxolane-2-yl) -L-tyrosine (8.44 g, 18.1 mmol) in methanol (160 mL), hydrogen peroxide (30 wt%, 8.59) was added under ice cooling. mL, 90.7 mmol), and stirred under ice-cooling for 30 minutes. A 10% aqueous sodium thiosulfate solution (40 mL) was added to the reaction solution, and the mixture was stirred under ice-cooling for 10 minutes, and further stirred at room temperature for 10 minutes. Water (160 mL) was added to the reaction solution, and methanol was distilled off under reduced pressure, followed by extraction with ethyl acetate (160 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 → 60/40) to obtain 6.45 g of the title compound (quantitative) as a pale yellow oily substance.

    (16d) methyl 3- (benzyloxy) -N- (tertiary butoxycarbonyl) -O- (methoxymethyl) -L-tyrosine    

Of methyl N- (tertiary butoxycarbonyl) -3-hydroxy-O- (methoxymethyl) -L-tyrosine (6.45 g, 18.1 mmol) obtained in Reference Example 16 (16c) To a solution of N, N-dimethylformamide (40 mL), benzyl bromide (2.58 mL, 21.7 mmol) and potassium carbonate (3.75 g, 27.2 mmol) were sequentially added, and the mixture was stirred at room temperature for 2 hours. Acetic acid (518 μL, 9.05 mmol) was added to the reaction solution, and after stirring at room temperature for 15 minutes, water (150 mL) was added, and extracted with ethyl acetate (150 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 97/3 → 50/50) to obtain 6.38 g of the title compound as a white solid substance (yield: 79%).

    (16e) (3S) -6- (benzyloxy) -7-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

Methyl 3- (benzyloxy) -N- (tertiary butoxycarbonyl) -O- (methoxymethyl) -L-tyrosine (6.38 g, To a solution of 14.3 mmol) in dichloromethane (50 mL), trifluoroacetic acid (21.9 mL, 286 mmol) was added and stirred at room temperature for 10 minutes. Next, after adding dichloromethane (150 mL), paraformaldehyde (1.36 g, 43.0 mmol) was added, and it stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (150 mL) and water (75 mL), and sodium bicarbonate (6.02 g, 71.6 mmol) was slowly added. Next, di-tertiary-butyl dicarbonate (4.69 g, 21.5 mmol) was added, and it stirred at room temperature for 3 hours. Water was added to the reaction solution, and extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 97/3 → 60/40) to obtain the title compound (4.84 g, yield 79%) as a colorless oily substance.

    (16f) (3S) -6- (benzyloxy) -7-[(trifluoromethanesulfonyl) oxy] -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2 -Tertiary butyl 3-methyl ester    

(3S) -6- (benzyloxy) -7-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl obtained in Reference Example 16 (16e) To a solution of methyl 3-methyl ester (9.00 g, 21.8 mmol) in dichloromethane (109 mL), under ice cooling, pyridine (2.63 mL, 32.7 mmol), trifluoromethanesulfonic anhydride (4.76 mL, 28.3 mmol) were sequentially added ) And stirred for 15 minutes under ice cooling. Water was added to the reaction solution, and the mixture was stirred under ice cooling for 10 minutes, and then extracted with dichloromethane (150 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 85/15 → 75/25) to obtain 11.8 g of the title compound as a colorless amorphous substance (yield: 99%).

    (16g) (3S) -6- (benzyloxy) -7- (4-hydroxybut-1-yn-1-yl) -3,4-dihydroisoquinoline-2,3 (1H) -di 2-tert-butyl 3-methyl formate    

(3S) -6- (benzyloxy) -7-{[(trifluoromethanesulfonyl) oxy] -3,4-dihydroisoquinoline-2 obtained in Reference Example 16 (16f), To a solution of 3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (13.2 g, 24.2 mmol) in N, N-dimethylformamide (30.2 mL), 3-butyne-1 was added -Alcohol (5.47 mL, 72.6 mmol), [1,1'-bis (diphenylphosphine) ferrocene] palladium (II) dichloromethane adduct (1.98 g, 2.42 mmol), iodination Copper (I) (0.92 g, 4.84 mmol) and triethylamine (26.9 mL, 194 mmol) were stirred at 80 ° C. for 5 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, and a saturated aqueous ammonium chloride solution (30 mL) was added, followed by filtration through celite, and washing with ethyl acetate. The filtrate was separated, and the aqueous layer was extracted with ethyl acetate (200 mL). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 → 60/40) to obtain 9.50 g of the title compound as a brown amorphous substance (yield 84%).

    (16h) (3S) -6- (benzyloxy) -7-((1E) -2- [4- (benzyloxy) phenyl] -4-hydroxybut-1-en-1-yl)- 3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

Under a nitrogen atmosphere, hydroxyl (cyclooctadiene) rhodium (I) dimer (263 mg, 0.58 mmol), potassium carbonate (2.92 g, 21.1 mmol), and (+/-)-2,2'-bis (di Phenylphosphine) -1,1'-binapinaphthalene (0.72g, 1.15mmol) (48 mL) solution, stirred at room temperature for 15 minutes, and then added (3S) -6- (benzyloxy) -7- (4-hydroxybut-1-yne-1) obtained in Reference Example 16 (16g) -Yl) -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (8.95 g, 19.2 mmol) After an alkane (48 mL) solution, 4-benzyloxyphenylboronic acid (8.77 g, 38.5 mmol) was added, and the mixture was stirred at 70 ° C for 4 hours. After the reaction solution was cooled to room temperature, ethyl acetate and water were added, and the mixture was filtered through celite and washed with ethyl acetate. The filtrate was separated, and the aqueous layer was extracted with ethyl acetate (200 mL). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 70/30 → 60/40) to obtain 10.19 g of the title compound as a pale brown amorphous substance (yield: 82%).

    (16i) (3S) -6-hydroxy-7- [4-hydroxy-2- (4-hydroxyphenyl) butyl] -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6- (benzyloxy) -7-{(1E) -2- [4- (benzyloxy) phenyl] -4-hydroxyl obtained in Reference Example 16 (16h) under a nitrogen atmosphere But-1-en-1-yl) -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (10.51 g, 16.2 mmol) in acetic acid To the ethyl acetate (81 mL) solution was added 7.5% palladium on carbon (wet, 50 wt%, 5.26 g), and the mixture was stirred at 50 ° C. for 3 hours under a hydrogen atmosphere. The reaction solution was cooled to room temperature, filtered, washed with ethyl acetate, and then the solvent was distilled off under reduced pressure. Then, a small amount of ethyl acetate was added, and then the operation was performed under reduced pressure twice to obtain a pale yellow color. Amorphous substance (7.63 g) of the title compound (quantitative).

(16j) (9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(3S) -6-hydroxy-7- [4-hydroxy-2- (4-hydroxyphenyl) butyl] -3,4-dihydroisoquinoline-2 obtained in Reference Example 16 (16i), To a solution of 3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (7.39 g, 15.7 mmol) in tetrahydrofuran (157 mL), triphenylphosphine (6.17 g, 23.5 mmol) was sequentially added under ice cooling. ), Bis (2-methoxyethyl) azodicarboxylate (5.51 g, 23.5 mmol), and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (200 mL), washed with water (× 2) and saturated brine (× 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 → 67/33) to obtain the title compound (6.32 g, yield 89%) as a white amorphous substance.

To obtain a non-mirror isomer mixture of the title compound, high-speed liquid chromatography (column: DAICEL CHIRALPAK IA, 0.46 × 25cm; mobile phase: n-hexane / 2-propanol = 90/10; flow rate; 1.0ml / min; temperature: 40 ° C; wavelength: 278 nm) analysis, confirming the first peak: RT = 22.29min; the second peak: RT = 32.12min.

    Reference Example 17    

(4R, 9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(17a) (4R) -4-benzyl-3-{[4-benzyloxy] phenyl} ethenyl} -1,3- Azolin-2-one

In a solution of 4-benzyloxyphenylacetic acid (4.51 g, 18.6 mmol) in dichloromethane (42 mL), under ice-cooling, sequentially add chloramphenicol (1.74 mL, 20.3 mmol), N, N-dimethylformaldehyde. Methylformamide (65 μL, 0.85 mmol) was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, a small amount of chloroform / n-hexane was added, and the solvent was distilled off again under reduced pressure to obtain acid chloride (colorless solid).

Next, at (R) -4-benzyl-2- To a solution of oxazolidone (3.00 g, 16.9 mmol) in tetrahydrofuran (56 mL), add n-butyl lithium in n-hexane solution (2.55 mol / L, 7.30 mL, 18.6 mmol) at -78 ° C and stir at the same temperature for 20 minute. Next, a solution of the previously prepared acid chloride in tetrahydrofuran (56 mL) was slowly added at -78 ° C, and after stirring at the same temperature for 10 minutes, the temperature was raised to room temperature. A saturated ammonium chloride aqueous solution was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9/1 → 2/1) to obtain 6.49 g of the title compound as a pale yellow oily substance (yield 96%).

(17b) (4R) -4-benzyl-3-{(2R) -4- (benzyloxy) -2- [4- (benzyloxy) phenyl] butylfluorenyl} -1,3- Azolin-2-one

(4R) -4-benzyl-3-{[4-benzyloxy] phenyl} ethenyl} -1,3- obtained in Reference Example 17 (17a) under a nitrogen atmosphere To a solution of oxazol-2-one (1.40 g, 3.49 mmol) in tetrahydrofuran (14 mL), a solution of sodium bis (trimethylsilyl) pyramine in tetrahydrofuran (1.0 M, 3.7 mL, 3.66 mmol) was added at -78 ° C. , Stir at the same temperature for 20 minutes. A solution of 2- (benzyloxy) ethyltrifluoromethanesulfonate (1.04 g, 3.66 mmol) in tetrahydrofuran (1.0 mL) described in US2017 / 152222 was added thereto, and after stirring at the same temperature for 3 minutes, under ice cooling, Stir for 50 minutes. The reaction solution was diluted with ethyl acetate, and a saturated aqueous ammonium chloride solution was added and separated. The organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 19/1 → 6/1 → 4/1) to obtain 1.87 g of the title compound as a yellow amorphous substance (yield 61%).

    (17c) (2R) -4- (benzyloxy) -2- [4- (benzyloxy) phenyl] butane-1-ol    

In a nitrogen atmosphere, in a solution of lithium aluminum hydride (160 mg, 4.22 mmol) in tetrahydrofuran (7 mL), under ice cooling, (4R) -4-benzyl-3-{(2R) ) -4- (benzyloxy) -2- [4- (benzyloxy) phenyl] butylfluorenyl} -1,3- A solution of oxazol-2-one (1.13 g, 2.11 mmol) in tetrahydrofuran (3.5 mL) was stirred at the same temperature for 1 hour. After the reaction solution was diluted with tetrahydrofuran, water (0.16 mL) and a 1N-sodium hydroxide aqueous solution (0.6 mL) were added under ice-cooling, followed by stirring at room temperature for 5 minutes. The reaction solution was filtered through celite, washed with tetrahydrofuran, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9/1 → 6/1 → 3/1) to obtain 563 mg of the title compound as a colorless oily substance (yield 74%).

    (17d) 1- (Benzyloxy) -4-[(2R) -4- (benzyloxy) -1-iodobutane-2-yl] benzene    

(2R) -4- (benzyloxy) -2- [4- (benzyloxy) phenyl] butane-1-ol (563 mg, 1.55 mmol) and tribenzene obtained in Reference Example 17 (17c) Phosphine (563 mg, 2.33 mmol) and imidazole (159 mg, 2.33 mmol) were dissolved in dichloromethane (7.7 mL), iodine (591 mg, 2.33 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with dichloromethane, washed with a 10% sodium bisulfite aqueous solution, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether / n-hexane = 1/1 was added to the residue, insoluble matter was filtered off, and after washing with diethyl ether / n-hexane = 1/1, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 30/1) to obtain 595 mg of the title compound as a colorless oily substance (yield: 81%).

    (17e) (3S) -6- (benzyloxy) -7-{(2R) -4- (benzyloxy) -2- [4- (benzyloxy) phenyl] butyl} -3,4 -Dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

Under reduced pressure, zinc powder (96mg, 1.47mmol) was heated with a heat gun for 5 minutes, and then cooled to room temperature. Under a nitrogen environment, N, N-dimethylformamide (0.84mL), Iodine (16 mg, 0.06 mmol) was stirred at room temperature for 5 minutes. Next, 1- (benzyloxy) -4-[(2R) -4- (benzyloxy) -1-iodobutane-2-yl] benzene (297 mg, 0.63) obtained in Reference Example 17 (17d) was added. mmol) of NN-dimethylformamide (0.3 mL) and iodine (16 mg, 0.06 mmol), and stirred at room temperature for 1 hour. Next, ginseng (dibenzylideneacetone) dipalladium (0) (19mg, 0.02mmol), 2-dicyclohexylphosphine-2 ', 6'-dimethoxybiphenyl (17mg, 0.04mmol) were sequentially added. ), Dry lithium chloride (36 mg, 0.84 mmol) and (3S) -6- (benzyloxy) -7-[(trifluoromethanesulfonyl) oxy]-obtained in Reference Example 16 (16f) 3,4-Dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (229 mg, 0.42 mmol) of N, N-dimethylformamide (0.84 mL ) The solution was stirred at 50 ° C. for 8 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with ethyl acetate, a saturated ammonium chloride aqueous solution was added, and insoluble matters were filtered through celite, and washed with ethyl acetate. The filtrate was separated, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 19/1 → 4/1) to obtain 222 mg of the title compound as a colorless oily substance (yield 71%).

    (17f) (3S) -6-hydroxy-7-{(2R) -4-hydroxy-2- [4-hydroxyphenyl] butyl} -3,4-dihydroisoquinoline-2,3 (1H ) -Dicarboxylic acid 2-tert-butyl 3-methyl ester    

2-tertiarybutyl 3-methyl (3S) -6- (benzyloxy) -7-{(2R) -4- (benzyloxy) -2- [obtained in Reference Example 17 (17e) 4- (benzyloxy) phenyl] butyl} -3,4-dihydroisoquinoline-2,3 (1H) -diformate (259mg, 0.63mmol) in ethyl acetate (1.1mL) Then, 10% palladium on carbon (wet, 50 wt%, 64 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3.5 hours. The reaction solution was filtered and washed with ethyl acetate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1 → 2/3) to obtain 34 mg of the title compound as a colorless solid (yield: 20%).

(17g) (4R, 9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(3S) -6-hydroxy-7-{(2R) -4-hydroxy-2- [4-hydroxyphenyl] butyl} -3,4-dihydroisoquine obtained in Reference Example 17 (17f) was used Porphyrin-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester was reacted in the same manner as described in Reference Example 16 (16j) to obtain the title compound as a colorless solid (yield 87%) ).

The obtained title compound was analyzed by high-speed liquid chromatography (column: DAICEL CHIRALPAK IA; mobile phase: n-hexane / 2-propanol) (holding time: 22.12 min).

    Reference Example 18     (18a) (4R, 9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tertiary butyl 9-methyl ester (peak 1) and (18b) (4S, 9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester (peak 2)

(9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 16 (16j) 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester, subjected to high-speed liquid chromatography (column: DAICEL CHIRALPAK IA; mobile phase: N-hexane / 2-propanol), and a white solid was obtained as a first peak in a yield of 42% (holding time: 22.29 min). As a result of comparison of the holding time, it was shown that (4R, 9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydrogen obtained from Reference Example 17 (17g) 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester has the same retention time. Further, (4S, 9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro was obtained as a white peak as a second isomer. [2,3-g] Isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester, yield 43% (holding time: 32.12min).

    Reference Example 19    

(9S) -4- (3-fluoro-4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 9-methyl 8-tert-butyl ester

    (19a) (3S) -6- (benzyloxy) -7-{(1E) -2- [4- (benzyloxy) -3-fluorophenyl] -4-hydroxybut-1-ene-1 -Yl) -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6- (benzyloxy) -7- (4-hydroxybut-1-yn-1-yl) -3,4-dihydroisoquinoline-2 obtained in Reference Example 16 (16g) was used , 3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester and (4-benzyloxy-3-fluorophenyl) boronic acid were reacted in the same manner as described in Reference Example 16 (16h), The title compound was obtained as a colorless solid (yield 59%).

    (19b) (3S) -7- [2- (3-fluoro-4-hydroxyphenyl) -4-hydroxybutyl] -6-hydroxy-3,4-dihydroisoquinoline-2,3 (1H ) -Dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6- (Benzyloxy) -7-{(1E) -2- [4- (benzyloxy) -3-fluorophenyl] -4-hydroxy group obtained in Reference Example 19 (19a) was used But-1-en-1-yl) -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester, as described in Reference Example 16 (16i) The reaction was carried out in the same manner to obtain the title compound (quantitative) as a colorless solid.

(19c) (9S) -4- (3-fluoro-4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(3S) -7- [2- (3-fluoro-4-hydroxyphenyl) -4-hydroxybutyl] -6-hydroxy-3,4-dihydroisoquine obtained in Reference Example 19 (19b) was used The phthaloline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester was reacted in the same manner as described in Reference Example 16 (16j) to obtain the title compound (76%) as a colorless solid.

    Reference example 20    

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(20a) (4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(4S, 9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 18 (18b) 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tertiary butyl 9-methyl ester (3.00g, 6.61mmol) in acetone (33mL), carbonic acid Potassium (2.74 g, 19.8 mmol) and 3,4-dichlorobenzyl bromide (1.88 mL, 13.2 mmol) were stirred at 50 ° C for 3.5 hours. The reaction solution was cooled to room temperature, and the precipitate was filtered off, washed with acetone, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 → 70/30) to obtain 4.05 g of the title compound (quantitative) as a white amorphous substance.

(20b) (4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7,8,9,10-eight hydrogen 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,9, obtained in Reference Example 20 (20a), 10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester (4.05 g, 6.61 mmol) in dichloromethane (44 mL), Add 4N-hydrochloric acid / 1,4-di (16.5 mL, 66.1 mmol) and stirred at room temperature for 3 hours. The reaction solution was diluted with water and dichloromethane, and potassium carbonate (10.0 g, 72.7 mmol) was slowly added, followed by extraction with dichloromethane (× 2). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.14 g of the title compound as a white solid (yield 93%).

    Reference example 21    

(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(21a) (9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 16 (16j) was used 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester was reacted in the same manner as described in Reference Example 20 (20a) to obtain The title compound as a white amorphous material (yield 83%).

(21b) (9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,9,10- obtained in Reference Example 21 (21a) Hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester was reacted in the same manner as described in Reference Example 20 (20b) to obtain The title compound was obtained as a white solid (94% yield).

    Reference example 22    

(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(22a) (9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(3S) -7- [2- (3-fluoro-4-hydroxyphenyl) -4-hydroxybutyl] -6-hydroxy-3,4-dihydroisoquine obtained in Reference Example 19 (19c) was used Porphyrin-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester was reacted in the same manner as described in Reference Example 20 (20a) to obtain the title compound as a colorless solid (yield 76%) ).

(22b) (9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -2,3,4,5,7,8,9,10 -Octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -2,3,4,5, obtained in Reference Example 22 (22a), 9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester was reacted in the same manner as described in Reference Example 20 (20b) to obtain The title compound as a colorless solid (yield 90%).

    Reference example 23    

(9S) -4- {4- [1- (3,4-dichlorophenyl) ethoxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(23a) (9S) -4- {4- [1- (3,4-dichlorophenyl) ethoxy] phenyl} -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 16 (16j) under a nitrogen atmosphere 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester (700 mg, 1.54 mmol), 1- (3,4-dichlorobenzene Methyl) ethanol (442 mg, 2.32 mmol) and tri-n-butylphosphine (577 mL, 2.32 mmol) in toluene (33 mL), and under ice cooling, 1,1'-azobis (N, N-dimethylformamide) was added. Methylformamide) (399 mg, 2.32 mmol), and then stirred at 40 ° C for 1 hour. The reaction solution was diluted with n-hexane / ethyl acetate = 1/1, and after filtering off insoluble matters, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 19/1 → 6/1) to obtain 937 mg of the title compound as a colorless solid (yield 97%).

(23b) (9S) -4- {4- [1- (3,4-dichlorophenyl) ethoxy] phenyl} -2,3,4,5,7,8,9,10-eight hydrogen 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4- [1- [3,4-dichlorophenyl) ethoxy] phenyl} -2,3,4,5,9, obtained in Reference Example 23 (23a), 10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester (1050 mg, 1.67 mmol) in chloroform (11 mL) solution, add trifluoro Acetic acid (5.57 mL) and stirred at room temperature for 1.5 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with chloroform, and an aqueous potassium carbonate solution was added to make it alkaline. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure to obtain 846 mg of the title compound as a colorless solid (yield 96%).

    Reference example 24    

(9S) -4- [4- (cyclohexylmethoxy) phenyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(24a) (9S) -4- [4- [1- (cyclohexylmethoxy) phenyl] -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 16 (16j) was used 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester and cyclohexanemethanol are the same as the method described in Reference Example 23 (23a) The reaction was carried out in situ to obtain the title compound as a colorless solid (71% yield).

(24b) (9S) -4- [4- (cyclohexylmethoxy) phenyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- [4- [1- (cyclohexylmethoxy) phenyl] -2,3,4,5,9,10-hexahydro obtained in Reference Example 24 (24a) was used 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester was reacted in the same manner as described in Reference Example 23 (23b) to obtain The title compound as a colorless solid (89% yield).

    Reference example 25    

(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(25a) (9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 16 (16j) was used 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester and 1- (3,4-dichlorophenyl) propane-1- The alcohol was reacted in the same manner as in the method described in Reference Example 23 (23a) to obtain the title compound as a colorless solid (yield 86%).

(25b) (9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4,5,7,8,9,10-eight hydrogen 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4- [1- [3 (4-dichlorophenyl) propoxy] phenyl} -2,3,4, obtained in Reference Example 25 (25a) under a nitrogen atmosphere, 5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester (133 mg, 0.208 mmol) in dichloromethane (1.38 mL), Under ice-cooling, trimethylsilane iodide (88uL, 0.623mmol) was added and stirred at the same temperature for 10 minutes. The reaction solution was diluted with chloroform, washed with a potassium carbonate solution, and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9/1 → 2/3) to obtain 101 mg of the title compound (yield 90%) as a colorless amorphous substance.

    Reference example 26    

(9S) -4- {4- [2- (Ethyloxy) -1- (3,4-dichlorophenyl) ethoxy] phenyl} -2,3,4,5,7,8 , 9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

    (26a) {(1- (3,4-dichlorophenyl) vinyl] oxy} (trimethyl) silane    

Under a nitrogen atmosphere, in a solution of 3 ', 4'-dichloroacetophenone (2.50 g, 13.2 mmol) and triethylamine (2.93 mL, 21.2 mmol) in dichloromethane (44 mL), under ice cooling, add Trimethylsilyl trifluoromethanesulfonate (3.35 mL, 18.5 mmol) and stirred at room temperature for 5 minutes. The reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate water, and washed with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / chloroform = 19/1) to obtain the title compound (3.22 g, yield 93%) as a colorless oily substance.

    (26b) 1- (3,4-dichlorophenyl) -2-hydroxyethyl ketone    

{[1- (3,4-dichlorophenyl) vinyl] oxy} (trimethyl) silane (3.22 g, 12.3 mmol) in dichloromethane (41 mL) obtained in Reference Example 26 (26a) To the solution, 3-chloroperbenzoic acid (30% by weight in water) (3.60 g, 13.6 mmol) was slowly added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with chloroform, and an aqueous sodium bisulfite solution was added and stirred for 10 minutes. Next, tetrahydrofuran and 1N-hydrochloric acid were added and stirred for 4 hours. The reaction solution was washed with an aqueous potassium carbonate solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To the residue was added n-hexane / ethyl acetate = 1/1, and the suspension was filtered and dried to obtain 1.60 g of the title compound as a colorless solid (yield: 63%).

    (26c) 2- (3,4-dichlorophenyl) -2-oxoethyl acetate    

1- (3,4-dichlorophenyl) -2-hydroxyethanone (1.60 g, 7.80 mmol) and 4-dimethylaminopyridine (191 mg, 1.56 mmol) obtained in Reference Example 26 (26b) To a solution of dichloromethane (39 mL), pyridine (816 uL, 10.1 mmol) and acetic anhydride (959 uL, 10.1 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 19/1 → 6/1) to obtain 1.88 g of the title compound as a colorless solid (yield: 98%).

    (26d) 2- (3,4-dichlorophenyl) -2-hydroxyethyl acetate    

Tetrahydrofuran (38 mL) / ethanol (9.5 mL) of 2- (3,4-dichlorophenyl) -2-oxoethyl acetate (1.88 g, 7.61 mmol) obtained in Reference Example 26 (26c) ) To the solution, under ice cooling, sodium borohydride (345 mg, 9.13 mmol) was added, and the mixture was stirred at the same temperature for 15 minutes. 1N-hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 6/1 → 3/1) to obtain 1.56 g of the title compound as a colorless oily substance (yield: 82%).

(26e) (9S) -4- {4- [2- (Ethyloxy) -1- (3,4-dichlorophenyl) ethoxy] phenyl} -2,3,4,5, 9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 16 (16j) was used 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester and 2- (3,4- Dichlorophenyl) -2-hydroxyethyl acetate was reacted in the same manner as described in Reference Example 23 (23a) to obtain the title compound as a colorless solid (yield 65%).

(26f) (9S) -4- {4- [2- (Ethyloxy) -1- (3,4-dichlorophenyl) ethoxy] phenylmethyl} -2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-formate

(9S) -4- {4- [2- (Ethyloxy) -1- (3,4-dichlorophenyl) ethoxy] phenyl} -2 obtained in Reference Example 26 (26e) was used. , 3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester was reacted in the same manner as described in Reference Example 25 (25b) to obtain The title compound is a colorless solid (73% yield).

    Reference example 27    

(9S) -4- {4-[(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl} -2,3,4,5,7,8, 9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(27a) (9S) -4-((3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy) phenyl) -2,3,4,5,9,10- Hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 16 (16j) was used 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester and (3,4-dichloro) obtained in Reference Example 15 (15a) Phenyl) (tetrahydropyran-4-yl) methanol was reacted in the same manner as described in Reference Example 25 (25a) to obtain the title compound as a white amorphous substance (yield: 82%).

(27b) (9S) -4- {4-[(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy) phenyl} -2,3,4,5,7 , 8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4-{(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl} -2,3,4 obtained in Reference Example 27 (27a) , 5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester was reacted in the same manner as described in Reference Example 23 (23b) to obtain The title compound (quantitative) as a white solid.

    Reference Example 28    

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4,5,7,8,9, 10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(28a) (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4,5,9,10 -Hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(4S, 9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 18 (18b) 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester and (1S) -1- (3,4) obtained in Reference Example 4 -Dichlorophenyl) propane-1-ol, which was reacted in the same manner as described in Reference Example 23 (23a) to obtain the title compound (yield 95%) as a white amorphous substance.

(28b) (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4,5,7,8 , 9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

Using (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28a), 4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester was reacted in the same manner as described in Reference Example 25 (25b) to obtain The title compound as a white amorphous substance (yield 97%).

    Reference Example 29    

(4S, 9S) -4- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl} -2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(29a) (4S, 9S) -4-((R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy) phenyl) -2,3,4, 5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(4S, 9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 18 (18b) 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester and (S)-(3, 4-Dichlorophenyl) (tetrahydropyran-4-yl) methanol was reacted in the same manner as described in Reference Example 23 (23a) to obtain the title compound as a white amorphous substance (yield 17%) ).

(29b) (4S, 9S) -4- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl) -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

8-Tributyl 9-methyl (4S, 9S) -4-((R)-(3,4-dichlorophenyl) (tetrahydropyran-4) obtained in Reference Example 29 (29a) was used -Yl) methoxy] phenyl} -2,3,4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -diformate was reacted in the same manner as described in Reference Example 25 (25b) to obtain the title of a white amorphous substance. Compound (91% yield).

    Reference example 30    

(4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3,4,5,7,8,9, 10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(30a) (4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3,4,5,9,10 -Hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester

(4S, 9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 18 (18b) 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester and (1S) -1- (3,4) obtained in Reference Example 6 -Difluorophenyl) propane-1-ol, which was reacted in the same manner as described in Reference Example 23 (23a) to obtain the title compound (yield 96%) as a white amorphous substance.

(30b) (4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3,4,5,7,8 , 9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

Using (4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 30 (30a), 4,5,9,10-hexahydro 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester was reacted in the same manner as described in Reference Example 25 (25b) to obtain The title compound (quantitative) as a white amorphous substance.

    Reference Example 31    

4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester methane sulfonate

N- (tertiary butoxycarbonyl) -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (8.71 g, 22.7 mmol) described in WO2010 / 114824 To a methanol (45 mL) solution, 4N-hydrochloric acid / 1,4-di Solution (57 mL, 227 mmol) and stirred at room temperature for 15 minutes. After the solvent was distilled off under reduced pressure, water was added, and potassium carbonate (3.45 g, 25.0 mmol) was slowly added. The reaction solution was extracted with dichloromethane / methanol = 9/1, and after drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (45 mL), methanesulfonic acid (1.43 mL, 22.0 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. After distilling off the solvent under reduced pressure, ethyl acetate (50 mL) was added to suspend the product, followed by filtration and washing with ethyl acetate to obtain 7.53 g of the title compound as a white solid (yield 87%).

    Reference example 32    

2-chloro-4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester dihydrochloride

    (32a) 2-chloro-4- (2,3-dimethylpyridin-4-yl) aniline    

Under a nitrogen atmosphere, 4-bromo-2,3-dimethylpyridine (3.00g, 16.1mmol) and 2-chloro-4- (4,4,5,5-tetramethyl-1,3,2- Dioxolane-2-yl) aniline (4.50 g, 17.7 mmol) To a solution of alkane (96.7mL) / water (24.2mL), potassium carbonate (6.69g, 48.4mmol) and [1,1'-bis (diphenylphosphine) ferrocene] palladium (II) dichloride were added. Methyl chloride adduct (1.32 g, 1.61 mmol) was stirred at 120 ° C for 4 hours. After the reaction solution was allowed to cool to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 → 20/80) to obtain 3.60 g of the title compound as a pale yellow solid (yield 96%).

    (32b) 4- (4-bromo-3-chlorophenyl) -2,3-dimethylpyridine    

To a solution of copper (II) bromide (4.32 g, 19.3 mmol) in acetonitrile (46.4 mL) was added tert-butyl nitrite (3.21 mL, 27.1 mmol), and the temperature was raised to 50 ° C. Next, a solution of 2-chloro-4- (2,3-dimethylpyridin-4-yl) aniline (3.60 g, 15.5 mmol) in acetonitrile (46.4 mL) obtained in Reference Example 32 (32a) was slowly added. , Stir at the same temperature for 2 hours. After the reaction solution was allowed to cool to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (× 3). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 → 40/60) to obtain 2.90 g of the title compound as a dark brown solid (yield: 63%).

    (32c) methyl N- (tertiary butoxycarbonyl) -2-chloro-4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Under reduced pressure, zinc (1.70 g, 26.0 mmol) was heated with a hot air fan for 3 minutes, and then left to cool to room temperature under a nitrogen atmosphere, and N, N-dimethylformamide (17.3 mL) was added. Next, iodine (bead-shaped, 330 mg, 1.30 mmol) was added and stirred for 5 minutes. Next, (2R) -2- (tertiary butoxycarbonylamino) -3-iodopropanoic acid methyl ester (3.14 g, 9.53 mmol) was added again, and iodine (beads, 330 mg, 1.30 mmol) was immediately added, and Stir at room temperature for 1 hour. Next, ginseng (dibenzylideneacetone) dipalladium (0) (397mg, 0.433mmol) and 2-dicyclohexylphosphine-2 ', 6'-dimethoxybiphenyl (356mg, 0.867mmol) were added. N-N-dimethylformamidine 4- (4-bromo-3-chlorophenyl) -2,3-dimethylpyridine (2.57 g, 8.67 mmol) obtained in Reference Example 32 (32b) was added Amine (10 mL) suspension was stirred at 50 ° C. for 2 hours under a nitrogen atmosphere. After the reaction solution was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate (× 3). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 → 50/50) to obtain 2.10 g of the title compound as a white solid (yield: 58%).

    (32d) 2-chloro-4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester dihydrochloride    

Methyl N- (tertiary butoxycarbonyl) -2-chloro-4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine obtained in Reference Example 32 (32c) (2.10 g, 5.01 mmol) in dichloromethane (25.1 mL), and under ice cooling, 4N-hydrochloric acid / 1,4-di After the alkane (10 mL, 40 mmol) solution was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, followed by azeotropy (× 2) with ethyl acetate, and then dichloromethane was added. The suspension was filtered and dried to obtain 1.70 g of the title compound as a yellow solid (yield 87%).

    Example 1    

N-{(9S) -4- {4- [cyclopropyl (3,4-dichlorophenyl) methoxy] phenyl} -1-methyl-8-[(pyridin-2-yl) methyl Yl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- (2 , 3-Dimethylpyridin-4-yl) -L-phenylalanine

    (1a) (9S) -1-methyl-4- {4-[(prop-2-en-1-yl) oxy] phenyl} -8-[(pyridin-2-yl) methyl)- 1,2,3,4,7,8,9,10-Octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(9S) -1-methyl-4- {4-[(prop-2-en-1-yl) oxy] phenyl] -1,2,3,4 obtained in Reference Example 2 (2k) , 7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (451mg, 1.10mmol) and pyridine-2-carboxaldehyde (221 μL , 2.21 mmol) in dichloromethane (5 mL), acetic acid (62 μL, 1.10 mmol) and sodium triacetoxyborohydride (699 mg, 3.30 mmol) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate aqueous solution, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 45: 55) to obtain 534 mg of the title compound as a yellow oily substance (yield 97%).

    (1b) (9S) -4- (4-hydroxyphenyl) -1-methyl-8-[(pyridin-2-yl) methyl] -1,2,3,4,7,8,9, 10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

Under a nitrogen atmosphere, (9S) -1-methyl-4- {4-[(prop-2-en-1-yl) oxy] phenyl} -8- [obtained in Example 1 (1a) (Pyridin-2-yl) methyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9 -To a solution of methyl formate (499 mg, 1.07 mmol) in tetrahydrofuran (25 mL), add Porphyrin (931 μL, 10.7 mmol) and (triphenylphosphine) palladium (0) (124 mg, 0.107 mmol), and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 80) to obtain 492 mg of the title compound (quantitative) as a brown oily substance.

    (1c) (9S) -4- {4- [cyclopropyl (3,4-dichlorophenyl) methoxy] phenyl} -1-methyl-8-[(pyridin-2-yl) methyl )] 1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(9S) -4- (4-hydroxyphenyl) -1-methyl-8-[(pyridin-2-yl) methyl] -1,2,3,4 obtained in Example 1 (1b) , 7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (43mg, 0.094mmol) and Reference Example 10 (10b) To a solution of the obtained cyclopropyl (3,4-dichlorophenyl) methanol (102 mg, 0.468 mmol) in toluene (1 mL) was added cyanomethylenetributylphosphine (102 mg, 0.468 mmol), and the temperature was 80 ° C. Stir for 2 hours. The reaction solution was left to cool to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50) to obtain 36 mg of the title compound as a brown oily substance ( Yield: 58%).

    (1d) (9S) -4- {4- [cyclopropyl (3,4-dichlorophenyl) methoxy] phenyl} -1-methyl-8-[(pyridin-2-yl) methyl Yl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(9S) -4- {4- [cyclopropyl (3,4-dichlorophenyl) methoxy] phenyl} -1-methyl-8-[( Pyridin-2-yl) methyl)] 1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9- To a solution of methyl formate (21 mg, 0.04 mmol) in methanol (0.25 mL) / tetrahydrofuran (0.25 mL) was added 2N-lithium hydroxide aqueous solution (0.5 mL, 1 mmol), and the mixture was stirred at room temperature for 16 hours. 1N-hydrochloric acid was added to the reaction solution, and water and saturated brine were added, followed by extraction with a mixed solvent of dichloromethane / methanol (9/1). After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 42 mg of the title compound (quantitative) as a yellow oily substance.

    (1e) N-{(9S) -4- {4- [cyclopropyl (3,4-dichlorophenyl) methoxy] phenyl} -1-methyl-8-[(pyridine-2- (Methyl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4 -(2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(9S) -4- {4- [cyclopropyl (3,4-dichlorophenyl) methoxy] phenyl} -1-methyl-8-[( Pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9- Formic acid (35mg, 0.055mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine dihydrochloride (29mg, 0.082mmol) N described in WO2010 / 114824 , N-dimethylformamidine (1mL) solution, triethylamine (23 μL, 0.164 mmol) and 4- (4,6-dimethoxy-1,3,5-trichloro -2-yl) -4-methyl Porphyrinium monohydrate (24 mg, 0.082 mmol) and stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50-0: 100-dichloromethane: methanol = 92: 8) to obtain 40 mg of the title compound as a yellow oily substance (yield 80). %).

    (1f) N-{(9S) -4- {4- [cyclopropyl (3,4-dichlorophenyl) methoxy] phenyl} -1-methyl-8-[(pyridine-2- (Methyl) -methyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4 -(2,3-dimethylpyridin-4-yl) -L-phenylalanine    

N-{(9S) -4- {4- [cyclopropyl (3,4-dichlorophenyl) methoxy] phenyl} -1-methyl-8 obtained in Example 1 (1e) -[(Pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline -9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (40 mg, 0.044 mmol) in tetrahydrofuran (0.25 mL) / methanol (0.5 mL) solution 2N-lithium hydroxide aqueous solution (0.25 mL, 0.50 mmol) was added and stirred at room temperature for 2.5 hours. 2N-hydrochloric acid and water were added to the reaction solution, and extracted with dichloromethane (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50-0: 100-dichloromethane: methanol = 85: 15), and the obtained solid was suspended in n-hexane: dichloromethane and collected by filtration. 25 mg of the title compound was obtained as a pale yellow solid (yield 63%).

    Example 2    

N-{(9S) -4- {4-[(5,6-dichloro-2,3-dihydro-1H-inden-1-yl) oxy] phenyl} -1-methyl-8- [(Pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline- 9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (2a) (9S) -4- {4-[(5,6-dichloro-2,3-dihydro-1H-inden-1-yl) oxy] phenyl} -1-methyl-8- [(Pyridin-2-yl) methyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline- 9-methyl formate    

(9S) -4- (4-hydroxyphenyl) -1-methyl-8-[(pyridin-2-yl) methyl] -1,2,3,4 obtained in Example 1 (1b) was used , 7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester and 5,6-dichloro- 2,3-Dihydro-1H-indene-1-ol was reacted in the same manner as in the method described in Example 1 (1c) to obtain the title compound as a pale brown oily substance (yield 40%).

    (2b) (9S) -4- {4-[(5,6-dichloro-2,3-dihydro-1H-inden-1-yl) oxy] phenyl} -1-methyl-8- [(Pyridin-2-yl) methyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline- 9-formic acid    

(9S) -4- {4-[(5,6-dichloro-2,3-dihydro-1H-inden-1-yl) oxy] phenyl}-obtained in Example 2 (2a) was used 1-methyl-8-[(pyridin-2-yl) methyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxyazepine [3,2 -g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 1 (1d) to obtain (quantitatively) the title compound as a yellow solid.

    (2c) N-{(9S) -4- {4-[(5,6-dichloro-2,3-dihydro-1H-inden-1-yl) oxy] phenyl} -1-methyl -8-[(pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] iso Quinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(9S) -4- {4-[(5,6-dichloro-2,3-dihydro-1H-inden-1-yl) oxy] phenyl}-obtained in Example 2 (2b) was used 1-methyl-8-[(pyridin-2-yl) methyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxyazepine [3,2 -g] isoquinoline-9-carboxylic acid was reacted in the same manner as in the method described in Example 1 (1e) to obtain the title compound as a yellow oily substance (yield 87%).

    (2d) N-{(9S) -4- {4-[(5,6-dichloro-2,3-dihydro-1H-inden-1-yl) oxy] phenyl} -1-methyl -8-[(pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] iso Quinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-{(9S) -4- {4-[(5,6-dichloro-2,3-dihydro-1H-inden-1-yl) oxy] benzene obtained in Example 2 (2c) } -1-methyl-8-[(pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [ 3,2-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as described in Example 1 (1f) The reaction was carried out in the same manner to obtain the title compound as a yellow solid (yield 37%).

    Example 3    

N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) -2-methoxyethoxy] phenyl} -1-methyl-8-[(pyridine- 2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (3a) (9S) -4- {4- [1- (3,4-dichlorophenyl) -2-methoxyethoxy] phenyl} -1-methyl-8-[(pyridine- 2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-formic acid Ester    

(9S) -4- (4-hydroxyphenyl) -1-methyl-8-[(pyridin-2-yl) methyl] -1,2,3,4 obtained in Example 1 (1b) was used , 7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester and 1- (3) obtained in Reference Example 7 (7c) , 4-Dichlorophenyl) -2-methoxyethanol was reacted in the same manner as in the method described in Example 1 (1c) to obtain the title compound as a light brown oily substance (yield 26%).

    (3b) (9S) -4- {4- [1- (3,4-dichlorophenyl) -2-methoxyethoxy] phenyl} -1-methyl-8-[(pyridine- 2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(9S) -4- {4- [1- [3,4-dichlorophenyl) -2-methoxyethoxy] phenyl} -1-methyl obtained in Example 3 (3a) was used -8-[(pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] iso The quinoline-9-formic acid methyl ester was reacted in the same manner as in the method described in Example 1 (1d) to obtain the title compound (quantitative) as a yellow oily substance.

    (3c) N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) -2-methoxyethoxy] phenyl} -1-methyl-8- [ (Pyridin-2-yl) methyl)]-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline- 9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(9S) -4- {4- [1- [3,4-dichlorophenyl) -2-methoxyethoxy] phenyl} -1-methyl obtained in Example 3 (3b) was used -8-[(pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] iso Quinoline-9-formic acid was reacted in the same manner as the method described in Example 1 (1e) to obtain the title compound as a pale yellow oily substance (yield 86%).

    (3d) N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) -2-methoxyethoxy] phenyl} -1-methyl-8- [ (Pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) -2-methoxyethoxy] phenyl} -1 obtained in Example 3 (3c) -Methyl-8-[(pyridin-2-yl) methyl)]-1,2,3,4,7,8,9,10-octahydro [1,4] oxyazepine [3,2 -g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, the same method as described in Example 1 (1f) The reaction was performed to obtain the title compound as a pale yellow solid (yield 41%).

    Example 4    

N-{(9S) -4- {4-[(3,4-dichlorophenyl) (phenyl) methoxy] phenyl} -1-methyl-8-[(pyridin-2-yl) Methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl} -4- ( 2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (4a) (9S) -4- {4-[(3,4-dichlorophenyl) (phenyl) methoxy] phenyl} -1-methyl-8-[(pyridin-2-yl) Methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(9S) -4- (4-hydroxyphenyl) -1-methyl-8-[(pyridin-2-yl) methyl] -1,2,3,4 obtained in Example 1 (1b) was used , 7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester and (3,4 -Dichlorophenyl) (phenyl) methanol, which was reacted in the same manner as the method described in Example 1 (1c) to obtain the title compound (yield: 53%) as a yellow oily substance.

    (4b) (9S) -4- {4-[(3,4-dichlorophenyl) (phenyl) methoxy] phenyl} -1-methyl-8-[(pyridin-2-yl) Methyl] -1,2,3,4,7,8,9,10-Octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(9S) -4- {4-[(3,4-dichlorophenyl) (phenyl) methoxy] phenyl} -1-methyl-8- [obtained in Example 4 (4a) was used (Pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9 -Methyl formate, which was reacted in the same manner as the method described in Example 1 (1d) to obtain the title compound (quantitative) as a yellow oily substance.

    (4c) N-{(9S) -4- {4-[(3,4-dichlorophenyl) (phenyl) methoxy] phenyl) -1-methyl-8-[(pyridine-2 -Yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl}- 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(9S) -4- {4-[(3,4-dichlorophenyl) (phenyl) methoxy] phenyl} -1-methyl-8- [obtained in Example 4 (4b) was used (Pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9 -Formic acid was reacted in the same manner as in the method described in Example 1 (1e) to obtain the title compound as a pale yellow oily substance (yield 80%).

    (4d) N-{(9S) -4- {4-[(3,4-dichlorophenyl) (phenyl) methoxy] phenyl) -1-methyl-8-[(pyridine-2 -Yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl}- 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-{(9S) -4- {4-[(3,4-dichlorophenyl) (phenyl) methoxy] phenyl} -1-methyl- obtained in Example 4 (4c) 8-[(pyridin-2-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquine Phenolin-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as described in Example 1 (1f) to obtain The title compound as a pale yellow solid (21% yield).

    Example 5    

N-{(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(3-fluorophenyl) methyl Group] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (5a) (4R, 9S) -8-[(3-fluorophenyl) methyl] -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8, 9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8,9,10 obtained in Reference Example 3 (3k) under a nitrogen atmosphere -Octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (4.50g, 12.2mmol) in dichloromethane (244mL), and acetic acid (2.10mL , 36.6 mmol) and 3-fluorobenzaldehyde (2.57 mL, 24.4 mmol) and stirred. Next, sodium triacetoxyborohydride (10.4 g, 48.9 mmol) was added, and it stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15-60: 40) to obtain 5.51 g of the title compound as a colorless oily substance (yield: 94%).

    (5b) (4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(3-fluorophenyl) formaldehyde Methyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-formic acid Ester    

(4R, 9S) -8-[(3-fluorophenyl) methyl] -4- (4-hydroxyphenyl) -1-methyl-1 obtained in Example 5 (5a) under a nitrogen atmosphere , 2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (1.00g, 2.10mmol) and (1S) -1- (3,4-dichlorophenyl) propane-1-ol (861 mg, 4.20 mmol) in a toluene (21.0 mL) / tetrahydrofuran (5.25 mL) solution obtained in Reference Example 4 was sequentially Add tri-n-butylphosphine (2.09 mL, 8.39 mmol) and 1,1'-azobis (N, N-dimethylformamide) (1.08 g, 6.30 mmol) and stir at room temperature for 1 hour . Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15-80: 20) to obtain 1.13 g of the title compound as a white amorphous substance (yield: 81%).

    (5c) (4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(3-fluorophenyl) formaldehyde ) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8-[( 3-fluorophenyl) methyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] iso To a solution of methyl quinoline-9-formate (6.20 g, 9.34 mmol) in methanol (93.4 mL) / tetrahydrofuran (93.4 mL), a solution of lithium hydroxide monohydrate (7.84 g, 187 mmol) in water (93.4 mL) was added. And stirred at 50 ° C for 1 hour. After the reaction solution was allowed to cool to room temperature, 1N-hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH to around 6.0, and then the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 5.67 g of the title compound as a pale yellow solid (yield: 93%).

    (5d) N-{(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(3-fluorobenzene (Methyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}-obtained in Example 5 (5c) under a nitrogen atmosphere 8-[(3-fluorophenyl) methyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxyazepine [3,2 -g] isoquinoline-9-carboxylic acid (4.67g, 7.19mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methane obtained in Reference Example 31 To a solution of a sulfonate (3.56 g, 9.35 mmol) in N, N-dimethylformamide (72.0 mL,), triethylamine (3.00 mL, 21.6 mmol) was added and stirred. Secondly, 4- (4,6-dimethoxy-1,3,5-trichloro -2-yl) -4-methyl Porphyrinium (2.57 g, 9.35 mmol) was stirred at room temperature for 2 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50-0: 100) to obtain 7.22 g of the title compound (quantitative) as a white amorphous substance.

    (5e) N-{(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(3-fluorobenzene (Methyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

N-{(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8 obtained in Example 5 (5d) -[(3-fluorophenyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxyazepine [3,2- g) Isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (8.94 g, 8.73 mmol) in methanol (87 mL) / tetrahydrofuran To a solution (87 mL), a solution of lithium hydroxide monohydrate (7.33 g, 175 mmol) in water (87 mL) was added and stirred at room temperature for 2 hours. After adding 1N-hydrochloric acid and a saturated sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to around 6, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 90: 10-70: 30) to obtain 7.11 g of the title compound as a pale yellow solid (yield 90%).

    Example 6    

(2S) -2-(([((4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8-[(3 -Fluorophenyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquine Porphyrin-9-carbonyl} amino) -3- [4- (2,3-dimethylpyridin-4-yl) phenyl] sodium propionate

N-{(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8 obtained in Example 5 (5d) -[(3-fluorophenyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxyazepine [3,2- g] Isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (150 mg, 0.166 mmol) in tetrahydrofuran (1.6 mL) / water (1.6 mL) of the solution, a 1N-sodium hydroxide aqueous solution (166.3 μL, 0.166 mmol) was added and stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was solidified with tetrahydrofuran / n-hexane to obtain 140 mg of the title compound as a white solid (yield 91%).

    Example 7    

N-{(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- [3-fluorophenyl) methyl ] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl}- 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine hydrochloride

N-{(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8 obtained in Example 5 (5d) -[(3-fluorophenyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxyazepine [3,2- g] Isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (150 mg, 0.166 mmol) in tetrahydrofuran (1.6 mL) / water To the solution (1.6 mL), 1N-hydrochloric acid (166 μL, 0.166 mmol) was added and stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was solidified with tetrahydrofuran / n-hexane to obtain 141 mg of the title compound as a yellow solid (yield 90% yield).

    Example 8    

N-{(4R, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8-[(3-fluorophenyl) methyl Group] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (8a) (4R, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8-[(3-fluorophenyl) formaldehyde Methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-formic acid Ester    

(4R, 9S) -8-[(3-fluorophenyl) methyl] -4- (4-hydroxyphenyl) -1-methyl-1,2,3 obtained in Example 5 (5a) was used , 4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester and (1S) -1 obtained in Reference Example 6 -(3,4-difluorophenyl) propane-1-ol was reacted in the same manner as in Example 5 (5b) to obtain the title compound as a white amorphous substance (yield 71%).

    (8b) (4R, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8-[(3-fluorophenyl) formaldehyde Yl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8-[( 3-fluorophenyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] iso The quinoline-9-formic acid methyl ester was reacted in the same manner as in the method described in Example 5 (5c) to obtain the title compound (quantitative) as a pale yellow solid.

    (8c) N-{(4R, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8-[(3-fluorobenzene (Methyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl) -8-[( 3-fluorophenyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] iso The quinoline-9-formic acid was reacted in the same manner as the method described in Example 5 (5d) to obtain the title compound (yield: 83%) as a pale yellow amorphous substance.

    (8d) N-{(4R, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8-[(3-fluorobenzene (Methyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-{(4R, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8 obtained in Example 8 (8c) -(3-fluorophenyl) methyl] -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g ] Isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 5 (5e). The title compound was obtained as a pale yellow solid (yield 98%).

    Example 9    

N-[(4R, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-form -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- (2, 3-dimethylpyridin-4-yl) -L-phenylalanine

    (9a) (4R, 9S) -8- (cyclobutylmethyl) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] Methacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8,9,10 obtained in Reference Example 3 (3k) under a nitrogen atmosphere -To a solution of octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (150 mg, 0.407 mmol) in dichloromethane (8.1 mL), acetic acid (70 μL, 1.22 mmol) and cyclobutanecarboxaldehyde (73 μL, 0.814 mmol), and stirred. Next, sodium triethoxyalkoxyborohydride (345 mg, 1.63 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15-60: 40) to obtain 157 mg of the title compound (yield: 88%) as a white amorphous substance.

    (9b) (4R, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-form Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -8- (cyclobutylmethyl) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4 obtained in Example 9 (9a) under a nitrogen atmosphere , 7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (157 mg, 0.359 mmol) and obtained in Reference Example 4 ( To a solution of 1S) -1- (3,4-dichlorophenyl) propane-1-ol (147 mg, 0.717 mmol) in toluene (3.6 mL) / tetrahydrofuran (896 μL), tri-n-butylphosphine ( 357 μL, 1.43 mmol) and 1,1′-azobis (N, N-dimethylformamide) (185 mg, 1.02 mmol), and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15-80: 20) to obtain 165 mg of the title compound (yield: 74%) as a white amorphous substance.

    (9c) (4R, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-form -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] obtained in Example 9 (9b) Phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid To a solution of methyl ester (164 mg, 0.263 mmol) in methanol (2.6 mL) / tetrahydrofuran (2.6 mL) was added a solution of lithium hydroxide monohydrate (221 mg, 5.26 mmol) in water (2.6 mL), and the mixture was stirred at 50 ° C for 1 hour. . After the reaction solution was allowed to cool to room temperature, 1N-hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH to around 6.0, and then the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 160 mg of the title compound (quantitative) as a pale yellow solid.

    (9d) N-[(4R, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}- 1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) obtained in Example 9 (9c) under a nitrogen atmosphere Propoxy] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline -9-formic acid (160 mg, 0.262 mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester methanesulfonate (130 mg, 0.341) obtained in Reference Example 31 To a solution of N, N-dimethylformamide (2.6 mL) in mmol), triethylamine (109 μL, 0.787 mmol) was added and stirred. Secondly, 4- (4,6-dimethoxy-1,3,5-trichloro -2-yl) -4-methyl Porphyrinium (101 mg, 0.341 mmol) was stirred at room temperature for 2 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50-0: 100) to obtain 183 mg of the title compound (yield: 80%) as a white amorphous substance.

    (9e) N-[(4R, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}- 1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine    

N-[(4R, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propene obtained in Example 9 (9d) Oxy] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline- 9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (183 mg, 0.209 mmol) in methanol (2.1 mL) / tetrahydrofuran (2.1 mL) Then, a solution of lithium hydroxide monohydrate (175 mg, 4.18 mmol) in water (2.1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After adding 1N-hydrochloric acid and a saturated sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to around 6, it was extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 90: 10-70: 30) to obtain 145 mg of the title compound as a pale yellow solid (yield 90%).

    Example 10    

N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8- (2-methyl Propyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl} -4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine

    (10a) (4R, 9S) -4- (4-hydroxyphenyl) -1-methyl-8- (2-methylpropyl) -1,2,3,4,7,8,9,10 -Methyl octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

Using isobutyl aldehyde, a reaction was carried out in the same manner as in the method described in Example 5 (5a) to obtain the title compound (yield: 70%) as a white amorphous substance.

    (10b) (4R, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -1-methyl-8- (2-methyl Propyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -4- (4-hydroxyphenyl) -1-methyl-8- (2-methylpropyl) -1,2,3,4 obtained in Example 10 (10a), 7,8,9,10-Octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as the method described in Example 5 (5b). The title compound was obtained as a white amorphous substance (yield: 81%).

    (10c) (4R, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -1-methyl-8- (2-methyl Propyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl obtained in Example 10 (10b) was used -8- (2-methylpropyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline- 9-Methyl formate was reacted in the same manner as in the method described in Example 5 (5c) to obtain the title compound as a pale yellow solid (yield 88%).

    (10d) N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8- ( 2-methylpropyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl obtained in Example 10 (10c) was used -8- (2-methylpropyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline- 9-formic acid was reacted in the same manner as in the method described in Example 5 (5d) to obtain the title compound as a pale yellow amorphous substance (yield: 82%).

    (10e) N-[(4R, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -1-methyl-8- ( 2-methylpropyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 obtained in Example 10 (10d) -Methyl-8- (2-methylpropyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] iso Quinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 5 (5e) to obtain The title compound is a pale yellow solid (93% yield).

    Example 11    

N-[(4R, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl- 1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] -4- (2,3- (Dimethylpyridin-4-yl) -L-phenylalanine

    (11a) (4R, 9S) -8-cyclopentyl-4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1 , 4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8,9,10 obtained in Reference Example 3 (3k) under a nitrogen atmosphere -Octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (200mg, 0.543mmol) in dichloromethane (10.9mL), acetic acid (93μL, 1.63 mmol) and cyclopentanone (144 μL, 1.63 mmol) and stirred. Next, sodium triethoxyalkoxyborohydride (460 mg, 2.17 mmol) was added, and it stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15-60: 40) to obtain 205 mg of the title compound (yield 86%) as a white amorphous substance.

    (11b) (4R, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl- 1,2,3,4,7,8,9,10-Octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -8-cyclopentyl-4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7 obtained in Example 11 (11a) under a nitrogen atmosphere , 8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (204mg, 0.467mmol) and (1S) obtained in Reference Example 4 To a solution of -1- (3,4-dichlorophenyl) propane-1-ol (192 mg, 0.934 mmol) in toluene (4.7 mL) / tetrahydrofuran (1.2 mL), tri-n-butylphosphine (466 μL) was sequentially added. , 1.87 mmol) and 1,1′-azobis (N, N-dimethylformamide) (241 mg, 1.40 mmol), and stirred at room temperature for 1 hour. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15-80: 20) to obtain 128 mg of the title compound (yield: 44%) as a white amorphous substance.

    (11c) (4R, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl- 1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 11 (11b) } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (127 mg, 0.204 mmol) in a methanol (2.0 mL) / tetrahydrofuran (2.0 mL) solution, a solution of lithium hydroxide monohydrate (171 mg, 4.07 mmol) in water (2.0 mL) was added, and stirred at 50 ° C. for 1 hour. After the reaction solution was allowed to cool to room temperature, 1N-hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH to around 6.0, and then the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 103 mg of the title compound as a pale yellow solid (yield 83%).

    (11d) N-{[((4R, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- ( 2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -8-cyclopentyl-4- {4-[(11) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 11 (11c) under a nitrogen atmosphere Yl] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Formic acid (102 mg, 0.167 mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate (83 mg, 0.218 mmol) obtained in Reference Example 31 To a solution of N, N-dimethylformamidine (1.7 mL), triethylamine (70 μL, 0.502 mmol) was added and stirred. Secondly, 4- (4,6-dimethoxy-1,3,5-trichloro -2-yl) -4-methyl Porphyrinium (64 mg, 0.218 mmol) and stirred at room temperature for 2 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50-0: 100) to obtain 112 mg of the title compound (yield 77%) as a white amorphous substance.

    (11e) N-{[((4R, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- ( 2,3-dimethylpyridin-4-yl) -L-phenylalanine    

N-{[((4R, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxylate) obtained in Example 11 (11d) Yl] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (112 mg, 0.128 mmol) in a solution of methanol (1.3 mL) / tetrahydrofuran (1.3 mL), A solution of lithium hydroxide monohydrate (107 mg, 2.56 mmol) in water (1.3 mL) was added and stirred at room temperature for 2 hours. 1N-hydrochloric acid and a saturated sodium bicarbonate aqueous solution were added to the reaction solution, and the pH was adjusted to around 6.0, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 90: 10-70: 30) to obtain 79 mg of the title compound as a pale yellow solid (yield 71%).

    Example 12    

N-[(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- ( 2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (12a) (4R, 9S) -4- [4- (benzyloxy) phenyl] -8- (cyclopentylmethyl) -1-methyl-1,2,3,4,7,8, 9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

Methyl (4R, 9S) -4- [4- (benzyloxy) phenyl] -1-methyl-1,3,4,7,9,10-octadecane obtained in Reference Example 3 (3j) Hydrogen [1,4] oxacridine [3,2-g] isoquinoline-9-dicarboxylate (210mg, 0.46mmol) and cyclopentanecarboxaldehyde (117μL, 1.10mmol) in dichloromethane (6mL ) To the solution, sodium triacetoxyborohydride (311 mg, 1.47 mmol) was added at room temperature and stirred for 3 hours. A saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and after stirring for 10 minutes, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 248 mg of the title compound (quantitative) as a pale yellow amorphous substance.

    (12b) (4R, 9S) -8- (cyclopentylmethyl) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8,9,10- Octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -4- [4- (benzyloxy) phenyl] -8- (cyclopentylmethyl) -1-methyl-1,2,3 obtained in Example 12 (12a) , 4,7,8,9,10-Octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (240mg, 0.44mmol) in ethyl acetate (4mL ) / Methanol (4 mL) solution, 10% palladium-carbon catalyst (wet, 50 wt%, 80 mg) was added, and stirred under a hydrogen atmosphere for 6 hours. After filtering through celite and distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain 176 mg of the title compound as a pale yellow amorphous substance. (88% yield).

    (12c) (4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -8- (cyclopentylmethyl) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7 obtained in Example 12 (12b) , 8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester (170mg, 0.38mmol) and (1S) obtained in Reference Example 4 To a solution of -1- (3,4-dichlorophenyl) propane-1-ol (108 mg, 0.53 mmol) in toluene (6 mL) was added tri-n-butylphosphine (100 μL, 0.49 mmol), 1,1 ' -Azobis (N, N-dimethylformamide) (84 mg, 0.49 mmol) and stirred at room temperature for 15 minutes. (1S) -1- (3,4-dichlorophenyl) propane-1-ol (54 mg, 0.26 mmol), tri-n-butylphosphine (52 μL, 0.25 mmol) and 1,1'-azo were added again Bis (N, N-dimethylformamidine) (45 mg, 0.25 mmol) was further stirred for 15 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to obtain 152 mg of the title compound as a colorless amorphous substance (yield: 63%).

    (12d) (4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 12 (12c) Yl] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -To a solution of methyl formate (150 mg, 0.24 mmol) in methanol (2 mL) / tetrahydrofuran (2 mL), a 1N-sodium hydroxide aqueous solution (706 μL, 0.71 mmol) was added and stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and water (6 mL) was added to the obtained residue. Then, 1N-hydrochloric acid was slowly added to adjust the pH to 4-5. After extraction with ethyl acetate, washing with saturated brine, and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 143 mg of the title compound as a pale yellow amorphous substance (yield 97%).

    (12e) N-[(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl]- 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 12 (12d) Yl] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Formic acid (140 mg, 0.22 mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate (103 mg, 0.27 mmol) obtained in Reference Example 31 In a solution of N, N-dimethylformamidine (4 mL), add N, N-diisopropylethylamine (59 μL, 0.34 mmol) and O- (azabenzimidazole-1) at room temperature. -Yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (94 mg, 0.25 mmol), and stirred for 2 hours. It was diluted with ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution, and then washed three times with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 90: 1) to obtain 200 mg of the title compound (quantitative) as a pale yellow amorphous substance.

    (12f) N-[(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl]- 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

N-[(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) obtained in Example 12 (12e) ) Propoxy] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquine Porphyrin-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (195 mg, 0.22 mmol) in methanol (2 mL) / tetrahydrofuran (2 mL) Then, a 1N-sodium hydroxide aqueous solution (657 μL, 0.66 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Add Dowex 50w-x8, adjust the pH of the solution to 4-5, and stir for 10 minutes. The insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1-20: 1) to obtain 143 mg of the title compound as a pale yellow solid (yield 75%).

    Example 13    

N-[(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- ( 2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (13a) (4R, 9S) -8- (cyclopentylmethyl) -4- (4-[(1R) -1- (3,4-difluorophenyl) propoxy 1phenyl) -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -8- (cyclopentylmethyl) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7 obtained in Example 12 (12b) , 8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester and (1S) -1- (3, 4-Difluorophenyl) propane-1-ol was reacted in the same manner as in the method described in Example 12 (12c) to obtain the title compound (yield 79%) as a white amorphous substance.

    (13b) (4R, 9S) -8- (cyclopentylmethyl) -4- (4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl) -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy) obtained in Example 13 (13a) was used Yl] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Methyl formate, which was reacted in the same manner as the method described in Example 12 (12d) to obtain the title compound (quantitative) as a pale yellow solid.

    (13c) N-[(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl]- 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy) obtained in Example 13 (13b) was used Yl] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Formic acid was reacted in the same manner as the method described in Example 12 (12e) to obtain the title compound (yield 72%) as a pale yellow amorphous substance.

    (13d) N-[(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl]- 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) obtained in Example 13 (13c) ) Propoxy] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquine Phenolin-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as in the method described in Example 12 (12f) to obtain The title compound as a pale yellow solid (86% yield).

    Example 14    

N-[(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (5,6-dichloropyridin-3-yl) propoxy] phenyl } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl]- 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (14a) (4R, 9S) -8- (cyclopentylmethyl) -4- (4-[(1R) -1- (5,6-dichloropyridin-3-yl) propoxy] phenyl } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -8- (cyclopentylmethyl) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7 obtained in Example 12 (12b) , 8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester and (1S) -1- (5, 6-Dichloropyridin-3-yl) propane-1-ol was reacted in the same manner as in the method described in Example 12 (12c) to obtain the title compound (yield: 82%) as a white amorphous substance.

    (14b) (4R, 9S) -8- (cyclopentylmethyl) -4- (4-[(1R) -1- (5,6-dichloropyridin-3-yl) propoxy] phenyl } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (5,6-dichloropyridin-3-yl) obtained in Example 14 (14a) was used ) Propoxy] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquine Methylline-9-formate was reacted in the same manner as in the method described in Example 12 (12d) to obtain the title compound as a pale yellow solid (yield: 82%).

    (14c) N-[(4R, 9S) -8- (cyclopentylmethyl) -4- (4-[(1R) -1- (5,6-dichloropyridin-3-yl) propoxy ] Phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9- Carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (5,6-dichloropyridin-3-yl) obtained in Example 14 (14b) was used ) Propoxy] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquine Porphyrin-9-formic acid was reacted in the same manner as in the method described in Example 12 (12e) to obtain the title compound as a pale yellow amorphous substance (yield: 64%).

    (14d) N-[(4R, 9S) -8- (cyclopentylmethyl) -4- (4-[(1R) -1- (5,6-dichloropyridin-3-yl) propoxy ] Phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9- Carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (5,6-dichloropyridine- 3-yl) propoxy] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxyazepine [3,2-g ] Isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 12 (12f). The title compound was obtained as a pale yellow solid (yield 61%).

    Example 15    

N-[(4R, 9S) -4- {4-[(1R) -1- (5-chloropyridin-3-yl) propoxy] phenyl} -8- (cyclopentylmethyl) -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- ( 2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (15a) (4R, 9S) -4- {4-[(1R) -1- (5-chloropyridin-3-yl) propoxy] phenyl} -8- (cyclopentylmethyl) -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -8- (cyclopentylmethyl) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7 obtained in Example 12 (12b) , 8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester and (1S) -1- (5- Chloropyridine-3-yl) propane-1-ol was reacted in the same manner as in the method described in Example 12 (12c) to obtain the title compound as a yellow oily substance (yield 60%).

    (15b) (4R, 9S) -4- {4-[(1R) -1- (5-chloropyridin-3-yl) propoxy] phenyl} -8- (cyclopentylmethyl) -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -4- {4-[(1R) -1- (5-chloropyridin-3-yl) propoxy] phenyl} -8- (ring obtained in Example 15 (15a) was used (Pentylmethyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9 -Methyl formate, which was reacted in the same manner as the method described in Example 12 (12d) to obtain the title compound (quantitative) as a pale yellow solid.

    (15c) N-[(4R, 9S) -4- {4-[(1R) -1- (5-chloropyridin-3-yl) propoxy] phenyl} -8- (cyclopentylmethyl ) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl]- 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -4- {4-[(1R) -1- (5-chloropyridin-3-yl) propoxy] phenyl} -8- (ring obtained in Example 15 (15b) was used (Pentylmethyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9 -Formic acid was reacted in the same manner as in the method described in Example 12 (12e) to obtain the title compound (yield 77%) as a pale yellow amorphous substance.

    (15d) N-[(4R, 9S) -4- {4-[(1R) -1- (5-chloropyridin-3-yl) propoxy] phenyl} -8- (cyclopentylmethyl ) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl]- 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -4- {4-[(1R) -1- (5-chloropyridin-3-yl) propoxy] phenyl} -8 obtained in Example 15 (15c) -(Cyclopentylmethyl) -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquine Phenolin-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as in the method described in Example 12 (12f) to obtain The title compound as a pale yellow solid (65% yield).

    Example 16    

N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8- (2,2 , 2-trifluoroethyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl ] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (16a) 3-[(2R) -2- (4-hydroxyphenyl) -5,8-dimethyl-2,3,4,5-tetrahydro-1,5-benzoxazepine- 7-yl] -N-methyl-N-{[(prop-2-en-1-yl) oxy] carbonyl} -L-alanine methyl ester    

(4R, 9S) -4- (4-hydroxyphenyl) -1-methyl-1,2,3,4,7,8,9,10 obtained in Reference Example 3 (3k) under a nitrogen atmosphere -To a solution of methyl octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-formate (3.50 g, 9.50 mmol) in ethyl acetate (95 mL), sodium bicarbonate ( A solution of 2.39 g, 28.5 mmol) in water (48 mL) was stirred vigorously. Next, diallyl dicarbonate (1.58 mL, 9.50 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate aqueous solution, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25-50: 50) to obtain 3.20 g of the title compound as a white amorphous substance (yield 74%).

    (16b) 3-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -5,8-dimethyl-2, 3,4,5-tetrahydro-1,5-benzoxazepine-7-yl] -N-methyl-N-{[(prop-2-en-1-yl) oxy] carbonyl} -L-alanine methyl ester    

Under a nitrogen atmosphere, 3-[(2R) -2- (4-hydroxyphenyl) -5,8-dimethyl-2,3,4,5-tetrahydro- obtained in Example 16 (16a) 1,5-benzoxazepin-7-yl] -N-methyl-N-{[(prop-2-en-1-yl) oxy] carbonyl} -L-alanine methyl ester (3.2 g, 7.1 mmol) and (1S) -1- (3,4-dichlorophenyl) propane-1-ol (2.9 g, 14 mmol) in toluene (71 mL) / tetrahydrofuran (18 mL) obtained in Reference Example 4 In order, tri-n-butylphosphine (7.0 mL, 28 mmol) and 1,1'-azobis (N, N-dimethylformamide) (3.7 g, 21 mmol) were sequentially added, and the mixture was stirred at room temperature. 1 hour. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20-60: 40) to obtain the title compound (3.91 g, yield: 86%) as a white amorphous substance.

    (16c) 3-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -5,8-dimethyl-2, 3,4,5-tetrahydro-1,5-benzoxazepine-7-yl] -N-methyl-L-alanine methyl ester    

3-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} obtained in Example 16 (16b) under a nitrogen atmosphere -5,8-dimethyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-7-yl] -N-methyl-N-{[(propyl-2- Alkenyl-1-yl) oxy] carbonyl} -L-alanine methyl ester (3.90 g, 6.10 mmol) in a solution of tetrahydrofuran (40.7 mL), added sequentially Porphyrin (2.13 mL, 24.4 mmol) and (triphenylphosphine) palladium (0) (705 mg, 0.610 mmol), and stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10-70: 30-50: 50) to obtain the title of 2.81 g of a white amorphous substance Compound (83% yield).

    (16d) 3-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -5,8-dimethyl-2, 3,4,5-tetrahydro-1,5-benzoxazepine-7-yl] -N-methyl-N- (2,2,2-trifluoroethyl) -L-alanine Ester    

3-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} obtained in Example 16 (16c) under a nitrogen atmosphere -5,8-dimethyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-7-yl] -N-methyl-L-alanine methyl ester (200mg, 0.310 mmol) in a solution of N, N-dimethylformamide (3.1 mL), and sodium bicarbonate (78 mg, 0.929 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate were sequentially added. (216 μL, 0.929 mmol) and stirred at room temperature for 2 hours. Further, sodium bicarbonate (78 mg, 0.929 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (216 µL, 0.929 mmol) were added, and the mixture was stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-70: 30) to obtain 119 mg of the title compound as a pale yellow oily substance (yield 60%).

    (16e) 3-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -5,8-dimethyl-2, 3,4,5-tetrahydro-1,5-benzoxazepine-7-yl] -N-methyl-N- (2,2,2-trifluoroethyl) -L-alanine    

Using 3-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -5,8 obtained in Example 16 (16d) -Dimethyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-7-yl] -N-methyl-N- (2,2,2-trifluoroethyl ) -L-alanine methyl ester was reacted in the same manner as in the method described in Example 5 (5c) to obtain the title compound (quantitative) as a pale yellow solid.

    (16f) N-[(4R, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -1-methyl-8- ( 2,2,2-trifluoroethyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline- 9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

Using 3-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -5,8 obtained in Example 16 (16e) -Dimethyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-7-yl] -N-methyl-N- (2,2,2-trifluoroethyl ) -L-alanine was reacted in the same manner as in the method described in Example 5 (5d) to obtain the title compound (yield 65%) as a pale yellow amorphous substance.

    (16g) N-[(4R, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -1-methyl-8- ( 2,2,2-trifluoroethyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline- 9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 obtained in Example 16 (16f) -Methyl-8- (2,2,2-trifluoroethyl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2 -g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, the same method as described in Example 5 (5e) The reaction was performed to obtain the title compound as a pale yellow solid (yield: 58%).

    Example 17    

N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8-propyl-1 , 2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-di (Methylpyridin-4-yl) -L-phenylalanine

    (17a) (4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8-propyl-1 , 2,3,4,7,8,9,10-Octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

3-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} obtained in Example 16 (16c) under a nitrogen atmosphere -5,8-dimethyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-7-yl] -N-methyl-L-alanine methyl ester (150mg, 0.270 mmol) in dichloromethane (8.1 mL), sequentially added acetic acid (70 μL, 1.22 mmol), propanal (31 μL, 0.540 mmol), and sodium triacetoxyborohydride (345 mg, 1.63 mmol), Stir at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-70: 30) to obtain 134 mg of the title compound as a white amorphous substance (yield: 83% yield).

    (17b) (4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8-propyl-1 , 2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy1phenyl} -1-methyl obtained in Example 17 (17a) was used -8-propyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester, The reaction was carried out in the same manner as the method described in Example 5 (5c) to obtain the title compound (quantitative) as a pale yellow solid.

    (17c) N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8-propane -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- (2, 3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl obtained in Example 17 (17b) was used -8-propyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid, and implementation The reaction was carried out in the same manner as described in Example 5 (5d) to obtain the title compound as a pale yellow amorphous substance (yield: 78%).

    (17d) N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8-propane -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- (2, 3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 obtained in Example 5 (5c) -Methyl-8-propyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl ] -4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 5 (5e) to obtain the title of a pale yellow solid. Compound (61% yield).

    Example 18    

N-[(4R, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- ( 2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (18a) (4R, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

Using cyclopropane formaldehyde, a reaction was carried out in the same manner as in the method described in Example 17 (17a) to obtain the title compound (yield 88%) as a white amorphous substance.

    (18b) (4R, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 -Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 18 (18a) was used Yl] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Methyl formate, which was reacted in the same manner as the method described in Example 5 (5c) to obtain the title compound (quantitative) as a pale yellow solid.

    (18c) N-[(4R, 9S) -8- (cyclopropylmethyl) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl]- 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 18 (18b) was used Yl] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Formic acid was reacted in the same manner as in the method described in Example 5 (5d) to obtain the title compound (yield: 85%) as a pale yellow amorphous substance.

    (18d) N-[(4R, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl]- 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) obtained in Example 18 (18c) ) Propoxy] phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquine Phenolin-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as described in Example 5 (5e) to obtain The title compound as a light yellow solid (88% yield).

    Example 19    

N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8-[(oxo -3-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl ] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (19a) (4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8-[(oxo -3-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid Methyl ester    

The reaction was carried out in the same manner as in Example 17 (17a) using oxazo-3-formaldehyde to obtain the title compound (yield 87%) as a white amorphous substance.

    (19b) (4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8-[(oxo -3-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl obtained in Example 19 (19a) was used -8-[(oxyfluoren-3-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] Methyl isoquinoline-9-formate was reacted in the same manner as in the method described in Example 5 (5c) to obtain the title compound (quantitative) as a pale yellow solid.

    (19c) N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8- [ (Oxo-3-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline- 9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl obtained in Example 19 (19b) was used -8-[(oxyfluoren-3-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] Isoquinoline-9-formic acid was reacted in the same manner as in the method described in Example 5 (5d) to obtain the title compound (quantitative) as a pale yellow amorphous substance.

    (19d) N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8- [ (Oxo-3-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline- 9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 obtained in Example 19 (19c) -Methyl-8-[(oxo-3-yl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2 -g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, the same method as described in Example 5 (5e) The reaction was performed to obtain the title compound as a pale yellow solid (yield 84%).

    Example 20    

N-[(4R, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl- 1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] -4- (2,3- (Dimethylpyridin-4-yl) -L-phenylalanine

    (20a) (4R, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl- 1,2,3,4,7,8,9,10-Octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

Using cyclobutanone, a reaction was carried out in the same manner as in the method described in Example 17 (17a) to obtain the title compound (quantitative) as a white amorphous substance.

    (20b) (4R, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl- 1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 20 (20a) was used } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester The reaction was carried out in the same manner as the method described in Example 5 (5c) to obtain the title compound (quantitative) as a pale yellow solid.

    (20c) N-[(4R, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1- Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] -4- (2 , 3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 20 (20b) was used } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid, and The reaction was carried out in the same manner as in the method described in Example 5 (5d) to obtain the title compound as a pale yellow amorphous substance (yield: 81%).

    (20d) N-[(4R, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1- Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] -4- (2 , 3-Dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 20 (20c) ] Phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9- Carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 5 (5e) to obtain a light yellow solid. The title compound (86% yield).

    Example 21    

N-[(4R, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl- 1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] -4- (2,3- (Dimethylpyridin-4-yl) -L-phenylalanine

    (21a) (4R, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl- 1,2,3,4,7,8,9,10-Octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

Under nitrogen atmosphere, at room temperature, 3-[(2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] obtained in Example 16 (16c) Phenyl} -5,8-dimethyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-7-yl] -N-methyl-L-alanine methyl ester (200 mg, 0.360 mmol) in methanol (2.0 mL), and sequentially added acetic acid (46 μL, 3.60 mmol), (1-ethoxycyclopropoxy) trimethylsilane (434 μL, 2.16 mmol), and cyano Sodium borohydride (114 mg, 1.82 mmol) was stirred at 60 ° C for 6 hours. The reaction solution was allowed to cool to room temperature, and then filtered, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50-25: 75) to obtain 207 mg of the title compound (yield 96%) as a white amorphous substance.

    (21b) (4R, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl- 1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 21 (21a) was used } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester The reaction was carried out in the same manner as the method described in Example 5 (5c) to obtain the title compound (quantitative) as a pale yellow solid.

    (21c) N-[(4R, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1- Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] -4- (2 , 3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 21 (21b) was used } -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid, and The reaction was carried out in the same manner as described in Example 5 (5d) to obtain the title compound (yield 74%) as a pale yellow amorphous substance.

    (21d) N-[(4R, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1- Methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] -4- (2 , 3-Dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 21 (21c) ] Phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9- Carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 5 (5e) to obtain a light yellow solid. The title compound (90% yield).

    Example 22    

N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8- (propane-2 -Yl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- ( 2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (22a) (4R, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -1-methyl-8- (propane-2 -Yl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

Using acetone, a reaction was carried out in the same manner as in the method described in Example 17 (17a) to obtain the title compound (quantitative) as a white amorphous substance.

    (22b) (4R, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -1-methyl-8- (propane-2 -Yl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl obtained in Example 22 (22a) was used -8- (propane-2-yl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Methyl formate, which was reacted in the same manner as the method described in Example 5 (5c) to obtain the title compound (quantitative) as a pale yellow solid.

    (22c) N-[(4R, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -1-methyl-8- ( Propane-2-yl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl]- 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl obtained in Example 22 (22b) was used -8- (propane-2-yl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9 -Formic acid was reacted in the same manner as in the method described in Example 5 (5d) to obtain the title compound as a pale yellow amorphous substance (yield 75%).

    (22d) N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-8- ( Propane-2-yl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl]- 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1 obtained in Example 22 (22c) -Methyl-8- (propane-2-yl) -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquine Phenolin-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as described in Example 5 (5e) to obtain The title compound as a pale yellow solid (85% yield).

    Example 23    

N-[(4R, 9S) -8-cyclohexyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-1 , 2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carbonyl] -4- (2,3-di (Methylpyridin-4-yl) -L-phenylalanine

    (23a) (4R, 9S) -8-cyclohexyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-1 , 2,3,4,7,8,9,10-Octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

Using cyclohexanone, a reaction was carried out in the same manner as in the method described in Example 17 (17a) to obtain the title compound (yield: 81%) as a pale yellow viscous oily substance.

    (23b) (4R, 9S) -8-cyclohexyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-methyl-1 , 2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(4R, 9S) -8-cyclohexyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} obtained in Example 23 (23a) was used -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid methyl ester, The reaction was carried out in the same manner as the method described in Example 5 (5c) to obtain the title compound (quantitative) as a pale yellow solid.

    (23c) N-[(4R, 9S) -8-cyclohexyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-form -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- (2, 3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(4R, 9S) -8-cyclohexyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} obtained in Example 23 (23b) was used -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carboxylic acid, and implementation The reaction was carried out in the same manner as in Example 5 (5d) to obtain the title compound as a pale yellow amorphous substance (yield: 57%).

    (23d) N-[(4R, 9S) -8-cyclohexyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -1-form -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl] -4- (2, 3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(4R, 9S) -8-cyclohexyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy]] obtained in Example 23 (23c) Phenyl} -1-methyl-1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl ] -4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 5 (5e) to obtain the title of a pale yellow solid. Compound (55% yield).

    Example 24    

N-{(4R, 9S) -1-ethenyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(3 -Fluorophenyl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxazepine [3,2-g] isoquinoline-9-carbonyl ] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (24a) (3S) -6- (ethylsulfonyl (3- [4- (benzyloxy) phenyl] -3-oxopropyl) amino) -7-{(tertiary butyl (di (Methyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester    

(3S) -6-({3- [4- (benzyloxy) phenyl] -3-oxopropylpropyl} amino) -7-{[tertiary Butyl (dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tert-butyl 3-methyl ester (4.4 g, 6.5 mmol ) In a solution of methylene chloride (30 mL), pyridine (840 μL, 10 mmol) was added, followed by dropwise addition of acetamidine chloride (510 μL, 7.2 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Saturated sodium bicarbonate water was added to the reaction solution, and after stirring for 10 minutes, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1 to 1: 1) to obtain the title compound (4.08 g, yield 87%) as a colorless amorphous substance.

    (24b) (3S) -6- (ethylfluorenyl (3- [4- (benzyloxy) phenyl] -3-oxopropyl) amino) -7-{(tertiary butyl (di (Methyl) silyl] oxy} -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester    

(3S) -6- (Ethylfluoride {3- [4- (benzyloxy) phenyl] -3-oxopropylpropyl} amino) -7- {obtained in Example 24 (24a) was used [Tertiary butyl (dimethyl) silyl] oxy} -3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tertiary butyl 3-methyl ester, with reference The reaction was carried out in the same manner as described in Example 3 (3j) to obtain the title compound as a colorless oily substance (yield 96%).

    (24c) (3S) -6- (Ethylfluorenyl (3- [4- (benzyloxy) phenyl] -3-sideoxypropyl) amino) -7-{[tertiary butyl (di (Methyl) silyl] oxy} -2-[(3-fluorophenyl) methyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester    

(3S) -6- (Ethylhydrazine {3- [4- (benzyloxy) phenyl] -3-oxopropylpropyl} amino) -7- {obtained in Example 24 (24b) was used [Tri-butyl (dimethyl) silyl] oxy} -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester and 3-fluorobenzaldehyde, as in Example 5 (5a) The described method was similarly reacted to obtain the title compound (quantitative) as a colorless amorphous substance.

    (24d) (3S) -6- (Ethyl {(3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl} amino) -7-{[tertiary butyl (Dimethyl) silyl] oxy} -2-[(3-fluorophenyl) methyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester    

(3S) -6- (Ethylfluoride {3- [4- (benzyloxy) phenyl] -3-oxopropylpropyl} amino) -7- {obtained in Example 24 (24c) was used [Tri-butyl (dimethyl) silyl] oxy} -2-[(3-fluorophenyl) methyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester The reaction was carried out in the same manner as in the method described in Reference Example 3 (3e) to obtain the title compound as a colorless amorphous substance (yield 61%).

    (24e) (3S) -6- (Ethyl {(3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl} amino) -2-[(3-fluorobenzene Methyl) -7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester    

(3S) -6- (Ethyl {{3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl} amino) -7 obtained in Example 24 (24d) was used -{[Tertiary butyl (dimethyl) silyl] oxy} -2-[(3-fluorophenyl) methyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid The methyl ester was reacted in the same manner as in the method described in Reference Example 3 (3f) to obtain the title compound (quantitative) as a colorless amorphous substance.

    (24f) (4R, 9S) -1-Ethyl-4- [4- (benzyloxy) phenyl] -8-[(3-fluorophenyl) methyl] -1,2,3,4 , 7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(3S) -6- (Ethyl {{3S) -3- [4- (benzyloxy) phenyl] -3-hydroxypropyl} amino) -2 obtained in Example 24 (24e) was used -[(3-fluorophenyl) methyl] -7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester was carried out in the same manner as in the method described in Reference Example 3 (3g). The reaction gave the title compound as a colorless amorphous substance (yield 63%).

    (24g) (4R, 9S) -1-Ethyl-8-[(3-fluorophenyl) methyl] -4- (4-hydroxyphenyl) -1,2,3,4,7,8 , 9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -1-Ethyl-4- [4- (benzyloxy) phenyl] -8-[(3-fluorophenyl) methyl]-obtained in Example 24 (24f) was used 1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester, and Example 12 (12b The method described in) was carried out in the same manner to obtain the title compound as a colorless amorphous substance (yield 91%).

    (24h) (9S) -1-ethenyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(3-fluoro Phenyl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester    

(4R, 9S) -1-Ethyl-8-[(3-fluorophenyl) methyl] -4- (4-hydroxyphenyl) -1,2, obtained from Example 24 (24 g) was used. 3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid methyl ester and (1S)-obtained in Reference Example 4 1- (3,4-dichlorophenyl) propane-1-ol was reacted in the same manner as in the method described in Example 5 (5b).

    (24i) (9S) -1-Ethyl-4--4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8-[(3-fluoro Phenyl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9-carboxylic acid    

(9S) -1-Ethyl-4-yl 4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}-obtained in Example 24 (24h) was used 8-[(3-fluorophenyl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquine Methyl phthaloline-9-formate was reacted in the same manner as in the method described in Example 5 (5c) to obtain the title compound as a colorless amorphous substance (yield 76%).

    (24j) N-[(9S) -1-Ethyl-4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8-[( 3-fluorophenyl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline-9- Carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(9S) -1-Ethyl-4-yl 4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}-obtained in Example 24 (24i) 8-[(3-fluorophenyl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquine Porphyrin-9-formic acid (365 mg, 0.54 mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester methane sulfonate (250 mg, 0.70mmol) in N, N-dimethylformamidine (8mL), N, N-diisopropylethylamine (281 μL, 1.61mmol) and O- (azabenzimidazole -1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (245 mg, 0.65 mmol), and stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution and saturated brine in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 60: 1) to obtain the title compound (378 mg, 47%) as a colorless amorphous substance.

    (24k) N-[(4R, 9S) -1-ethenyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- [(3-fluorophenyl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g] isoquinoline- 9-yl] carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(9S) -1-ethenyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] benzene obtained in Example 24 (24j) } -8-[(3-fluorophenyl) methyl] -1,2,3,4,7,8,9,10-octahydro [1,4] oxacridine [3,2-g ] Isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 5 (5e). The title compound was obtained as a colorless solid (yield 83%).

    Example 25    

N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- (1-benzene Propyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine

    (25a) (3S) -7- (benzyloxy) -2- (tertiary butoxycarbonyl) -3- (methoxycarbonyl) -1,2,3,4-tetrahydroisoquinoline-6 -Formic acid    

(3S) -7- (benzyloxy) -6-methylamino-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 2-tris obtained in Reference Example 13 (13h) To a solution of butyl 3-methyl ester (15.4 g, 36.2 mmol) in acetonitrile (300 mL), a solution of sodium dihydrogen phosphate dihydrate (3.4 g, 22 mmol) in water (20 mL) and hydrogen peroxide water (5.1 mL, 54 mmol). Next, a solution of sodium chlorite (6.6 g, 72 mmol) in water (130 mL) was added dropwise under ice cooling, and the mixture was directly stirred at the same temperature for 1 hour, then raised to room temperature, and stirred for 1 hour. The reaction solution was ice-cooled again, and a 20% sodium bisulfite aqueous solution (110 mL) was slowly added until the exotherm subsided, and stirred for 15 minutes. The reaction solution was extracted twice with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 13.4 g of the title compound as a colorless solid (yield: 84%).

    (25b) (3S) -2- (tertiary butoxycarbonyl) -7-hydroxy-3- (methoxycarbonyl) -1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid    

(3S) -7- (benzyloxy) -2- (tertiary butoxycarbonyl) -3- (methoxycarbonyl) -1,2,3,4- obtained in Example 25 (25a) was used Tetrahydroisoquinoline-6-formic acid was reacted in the same manner as in the method described in Reference Example 13 (13i) to obtain the title compound (quantitative) as a colorless amorphous substance.

    (25c) (3S) -7-hydroxy-3- (methoxycarbonyl) -2-{[(prop-2-en-1-yl) oxy] carbonyl} -1,2,3,4-tetra Hydroisoquinoline-6-carboxylic acid    

(3S) -2- (tertiary butoxycarbonyl) -7-hydroxy-3- (methoxycarbonyl) -1,2,3,4-tetrahydroisoquine obtained in Example 25 (25b) To a solution of chloro-6-formic acid (10 g, 29 mmol) in dichloromethane (150 mL), 4N-hydrochloric acid / 1,4-di Solution (70 mL, 0.2 mol) and stirred for 16 hours. The solvent was distilled off under reduced pressure, and ethyl acetate (250 mL) and water (100 mL) were added to the obtained residue. Then, sodium bicarbonate (12 g, 0.14 mol) was slowly added, and then diallyl dicarbonate (5 mL) was added. , 30 mmol), and stirred for 2 hours. After the reaction solution was ice-cooled, 1N-hydrochloric acid was added to adjust the pH to 3-4, and then extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 6.8 g of the title compound as a colorless solid (yield 71%).

    (25d) (3S) -6-{[((2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2-hydroxyethyl ] (Methyl) aminomethyl} -7-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 3-methyl 2-prop-2-en-1-yl ester    

(3S) -7-hydroxy-3- (methoxycarbonyl) -2-{[(prop-2-en-1-yl) oxy] carbonyl} -1 obtained in Example 25 (25c), 2,3,4-tetrahydroisoquinoline-6-carboxylic acid (500 mg, 1.49 mmol), (1R) -1- {4-[(1R) -1- (3, 4-Dichlorophenyl) propoxy] phenyl} -2- (methylamino) ethanol (581 mg, 1.64 mmol) and 1-hydroxybenzotriazole (201 mg, 1.49 mmol) N, N-di To a solution of methylformamide (10 mL), N, N-diisopropylethylamine (312 μL, 1.79 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl were added at room temperature. After carbodiimide hydrochloride (343 mg, 1.79 mmol), the temperature was raised to 50 ° C, and the mixture was stirred for 1 hour. After the reaction solution was allowed to cool to room temperature, it was diluted with ethyl acetate, washed once with a saturated sodium bicarbonate aqueous solution, washed three times with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (10 mL), and potassium carbonate (124 mg, 0.89 mmol) was added under ice-cooling, followed by stirring at the same temperature for 20 minutes. The reaction solution was warmed to room temperature, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 60: 1) to obtain 740 mg of the title compound as a colorless amorphous substance (yield: 74%).

    (25e) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-5- pendant- 3,4,5,7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 8-methyl9-propane -2-en-1-yl ester    

(3S) -6-{[((2R) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) obtained in Example 25 (25d) } -2-hydroxyethyl] (methyl) aminomethyl} -7-hydroxy-3,4-dihydroisoquinoline-2,3 (1H) -dicarboxylic acid 3-methyl 2-propan-2 -Ene-1-yl ester (740 mg, 1.10 mmol) in a solution of tetrahydrofuran (10 mL), and under ice cooling, triphenylphosphine (578 mg, 2.20 mmol) and bis (2-methoxyethyl) azodimethyl After the acid ester (387 mg, 1.65 mmol), it was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1-1: 3) to obtain 955 mg of a mixture containing the title compound, which was directly delivered to the next reaction.

    (25f) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-5- pendant- 2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

Including (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 25 (25e) Phenyl-5- pendantoxy-3,4,5,7,8,10-hexahydro [1,4] oxazepine [6,7-g] isoquinoline-8,9 (2H) -di To a solution of 8-methyl 9-prop-2-en-1-yl formate (955 mg) in tetrahydrofuran (20 mL) was added tetrakis (triphenylphosphine) palladium (0) (118 mg, 0.10 mmol) and Porphyrin (0.36 mL, 4.1 mmol) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 90: 1) to obtain 511 mg of the title compound as a colorless amorphous substance (yield: 81%).

    (25g) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-5- pendantoxy- 9- (1-phenylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8 -Methyl formate    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 25 (25f) -5-Pendantoxy-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester (380mg, 0.67mmol) and 1-bromopropylbenzene (400mg, 2.00mmol) in N, N-dimethylformamide (5mL), sodium bicarbonate (224mg, 2.67mmol) was added, and Stir for 4 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain 218 mg of the title compound as a colorless amorphous substance (yield: 48%).

    (25h) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- (1-benzene Propyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 25 (25g) -5-Pentyloxy-9- (1-phenylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxyacridine [6,7- g] A solution of methyl isoquinoline-8-formate (440 mg, 0.64 mmol) in dichloromethane (10 mL), trifluoromethanesulfonic anhydride (129 μL, 0.77 mmol) was added at room temperature and stirred for 5 minutes, then diethyl 1,4-dihydro-2,6-dimethyl-3,5-picolinate (405 mg, 1.60 mmol), and stirred at room temperature for 3 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and after stirring for 10 minutes, it was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 362 mg of the title compound as a colorless amorphous substance (yield 84%).

    (25i) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- (1-benzene Propyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 25 (25h) -9- (1-phenylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- A solution of methyl 8-formate (360 mg, 0.53 mmol) in methanol (4 mL) / tetrahydrofuran (4 mL), a 1N-sodium hydroxide aqueous solution (1.6 mL, 1.60 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ice water (10 mL), 1N-hydrochloric acid was added, the pH was adjusted to 4-5, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1 ~ 3: 1) to obtain 320 mg of the title compound as a colorless amorphous substance (yield 91%).

    (25j) N-[(2S, 8S) -2- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-methyl-9- ( 1-phenylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 25 (25i) -9- (1-phenylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- 8-formic acid (310mg, 0.47mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine dihydrochloride (218mg, 0.61mmol) described in WO2010 / 114824 To a solution of N, N-dimethylformamidine (8 mL), add N, N-diisopropylethylamine (205 μL, 1.17 mmol) and O- (azabenzimidazole-1) at room temperature. -Yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (232 mg, 0.61 mmol), and stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 70: 1) to obtain 261 mg of the title compound as a colorless amorphous substance (yield: 60%).

    (25k) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- ( 1-phenylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 obtained in Example 25 (25j) -Methyl-9- (1-phenylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] iso Quinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (260mg, 0.28mmol) in methanol (2mL) / tetrahydrofuran (2mL) To the solution, a 1N-sodium hydroxide aqueous solution (1.12 mL, 1.12 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Dowex 50w-x8 was added to the reaction solution, the pH was adjusted to 3-4, and after stirring for 10 minutes, it was filtered, and the solvent was distilled off under reduced pressure. Ethyl acetate and n-hexane were added to the residue and solidified to obtain 15 mg of the title compound as a colorless solid (yield 84%).

    Example 26    

N-[(2S, 8S) -9-benzyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-2 , 3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-di (Methylpyridin-4-yl) -L-phenylalanine

    (26a) (2S, 8S) -9-benzyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-5 -Pendantoxy-2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 25 (25f) -5-Pendantoxy-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester (265 mg, 0.47 mmol) and benzaldehyde (71 μL, 0.70 mmol) in a dichloromethane (4 mL) solution, acetic acid (27 μL, 0.47 mmol) and sodium triacetoxyborohydride (296 mg, 1.40 mmol) were added and stirred 48 hours. A saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution, and after stirring for 10 minutes, it was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 188 mg of the title compound as a colorless amorphous substance (yield 61%).

    (26b) (2S, 8S) -9-benzyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-2 , 3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -9-benzyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} obtained in Example 26 (26a) was used 4-methyl-5- pendantoxy-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- Methyl 8-formate was reacted in the same manner as in the method described in Example 25 (25h) to obtain the title compound as a colorless amorphous substance (yield 56%).

    (26c) (2S, 8S) -9-benzyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-2 , 3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -9-benzyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} obtained in Example 26 (26b) was used 4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid methyl ester, The reaction was carried out in the same manner as the method described in Example 25 (25i) to obtain the title compound (quantitative) as a colorless amorphous substance.

    (26d) N-[(2S, 8S) -9-benzyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-methyl -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2, 3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -9-benzyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} obtained in Example 26 (26c) was used 4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid, and implementation The reaction was carried out in the same manner as in Example 25 (25j) to obtain the title compound as a colorless amorphous substance (yield: 84%).

    (26e) N-[(2S, 8S) -9-benzyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2, 3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -9-benzyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy]] obtained in Example 26 (26d) Phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl ] -4- (2,3-dimethylpyridin-4-yl) -L-phenylpropylcarbamate was reacted in the same manner as the method described in Example 25 (25k) to obtain the title compound as a colorless solid. (67% yield).

    Example 27    

N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9-[(2- (Methylphenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinolin-8-yl ] Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (27a) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-methyl-9-[(2- (Methylphenyl) methyl] -5- pendantoxy-2,3,4,5,7,8,9,10-octahydro [1,4] oxyazepine [6,7-g] iso Quinoline-8-methyl formate    

Using o-tolualdehyde, the reaction was carried out in the same manner as in the method described in Example 26 (26a) to obtain the title compound as a colorless amorphous substance (yield: 75%).

    (27b) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9-[(2- (Methylphenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid Methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 27 (27a) was used -9-[(2-methylphenyl) methyl] -5-oxo-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [ 6,7-g] isoquinoline-8-carboxylic acid methyl ester was reacted in the same manner as the method described in Example 25 (25h) to obtain the title compound as a colorless amorphous substance (yield: 77%).

    (27c) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9-[(2- (Methylphenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 27 (27b) was used -9-[(2-methylphenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] The methyl isoquinoline-8-formate was reacted in the same manner as in the method described in Example 25 (25i) to obtain the title compound as a colorless amorphous substance (yield: 94%).

    (27d) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- [ (2-methylphenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- 8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 27 (27c) was used -9-[(2-methylphenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] Isoquinoline-8-formic acid was reacted in the same manner as the method described in Example 25 (25j) to obtain the title compound (yield: 85%) as a colorless amorphous substance.

    (27e) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- [ (2-methylphenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- 8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 obtained in Example 27 (27d) -Methyl-9-[(2-methylphenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7 -g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, the same method as described in Example 25 (25k) The reaction was performed to obtain the title compound as a colorless solid (yield 67%).

    Example 28    

N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9-[(5- Methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(28a) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9-[(5- Methyl-1,2- Azol-3-yl) methyl] -5- pendantoxy-2,3,4,5,7,8,9,10-octahydro [1,4] oxyazepine [6,7-g] Methyl isoquinoline-8-formate

Use 5-methyl The azole-3-carbaldehyde was reacted in the same manner as in the method described in Example 26 (26a) to obtain the title compound as a colorless amorphous substance (yield: 84%).

(28b) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9-[(5- Methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Methyl formate

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 28 (28a) was used -9-[(5-methyl-1,2- Azol-3-yl) methyl] -5- pendantoxy-2,3,4,5,7,8,9,10-octahydro [1,4] oxyazepine [6,7-g] Isoquinoline-8-formic acid methyl ester was reacted in the same manner as described in Example 25 (25h) to obtain the title compound (yield 26%) as a pale yellow amorphous substance.

(28c) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9-[(5- Methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Formic acid

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 28 (28b) was used -9-[(5-methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Methyl formate was reacted in the same manner as the method described in Example 25 (25i) to obtain the title compound as a colorless amorphous substance (yield: 98%).

(28d) N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- [ (5-methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 28 (28c) was used -9-[(5-methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Formic acid was reacted in the same manner as in the method described in Example 25 (25j) to obtain the title compound (purity: 85%, yield: 99%) as a pale yellow amorphous substance.

(28e) N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- [ (5-methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 obtained in Example 28 (28d) -Methyl-9-[(5-methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 25 (25k) to obtain the title as a colorless solid. Compound (58% yield).

    Example 29    

N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[(3-fluorophenyl) methyl Yl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (29a) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[(3-fluorophenyl) formaldehyde Yl] -4-methyl-5- pendantoxy-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquine Methyl-8-carboxylate    

Using 3-fluorobenzaldehyde, the reaction was carried out in the same manner as described in Example 26 (26a) to obtain the title compound as a colorless solid (yield: 82%).

    (29b) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -9-[(3-fluorophenyl) formaldehyde Methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-formic acid Ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[( 3-fluorophenyl) methyl] -4-methyl-5- pendantoxy-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6 , 7-g] isoquinoline-8-carboxylic acid methyl ester was reacted in the same manner as the method described in Example 25 (25h) to obtain the title compound as a colorless solid (yield: 44%).

    (29c) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[(3-fluorophenyl) formaldehyde Yl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -9-[( 3-fluorophenyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] iso The quinoline-8-formic acid methyl ester was reacted in the same manner as the method described in Example 25 (25i) to obtain the title compound as a colorless solid (yield: 99%).

    (29d) N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[(3-fluorobenzene (Methyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[( 3-fluorophenyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] iso Quinoline-8-formic acid was reacted in the same manner as the method described in Example 25 (25j) to obtain the title compound as a colorless solid (yield 46%).

    (29e) N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[(3-fluorobenzene (Methyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-{[((2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl)} obtained in Example 29 (29d) 9-[(3-fluorophenyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7 -g] isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, the same method as described in Example 25 (25k) The reaction was performed to obtain the title compound as a colorless solid (yield 68%).

    Example 30    

N-[(2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 -Methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- ( 2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (30a) (2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 -Methyl-5- pendantoxy-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Methyl formate    

Using cyclopentanecarboxaldehyde, the reaction was carried out in the same manner as in the method described in Example 26 (26a) to obtain the title compound as a colorless amorphous substance (yield: 63%).

    (30b) (2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 -Methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 30 (30a) was used Yl] phenyl} -4-methyl-5- pendantoxy-2,3,4,5,7,8,9,10-octahydro [1,4] oxyazepine [6,7-g ] Isoquinoline-8-carboxylic acid methyl ester was reacted in the same manner as the method described in Example 25 (25h) to obtain the title compound (yield: 92%) as a pale yellow amorphous substance.

    (30c) (2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 -Methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

Using (2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 30 (30b) Yl] phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8 -Methyl formate, which was reacted in the same manner as described in Example 25 (25i) to obtain the title compound as a colorless solid (yield 86%).

    (30d) N-[(2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl } -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl]- 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 30 (30c) was used Yl] phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8 -Formic acid was reacted in the same manner as the method described in Example 25 (25j) to obtain the title compound as a pale yellow amorphous substance (yield: 51%).

    (30e) N-[(2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl } -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl]- 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) obtained in Example 30 (30d) ) Propoxy] phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquine Phenolin-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as described in Example 25 (25k) to obtain The title compound as a colorless solid (55% yield).

    Example 31    

N-{(2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9-[(pyridine- 2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (31a) (2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-methyl-3,4,5, 7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tert-butyl 8-methyl ester    

(2S, 8S) -2- (4-hydroxyphenyl) -4-methyl-3,4,5,7,8,10-hexahydro [1,4] obtained in Reference Example 13 (13q) Oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tert-butyl 8-methyl ester (125 mg, 0.27 mmol) and (1R ) -1- (3,4-dichlorophenyl) propane-1-ol (82 mg, 0.40 mmol) in toluene (1.8 mL), tri-n-butylphosphine (100 μL, 0.40 mmol), 1, After 1'-azobis (N, N-dimethylformamidine) (69 mg, 0.40 mmol), it was stirred at 40 ° C for 1.5 hours. After the reaction solution was allowed to cool to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1-1: 1) to obtain 137 mg of the title compound as a colorless solid (yield: 78%).

    (31b) (2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-methyl-2,3,4, 5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

9-tertiary butyl 8-methyl (2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorobenzene) obtained in Example 31 (31a) under a nitrogen atmosphere Propyl) propoxy] phenyl} -4-methyl-3,4,5,7,8,10-hexahydro [1,4] oxazepine [6,7-g] isoquinoline-8 , 9 (2H) -diformate (172mg, 0.262mmol) in dichloromethane (1.8mL), and under ice cooling, trimethylsilyl iodide (90 μL, 0.656mmol) was added and stirred at the same temperature for 10 minute. The reaction solution was diluted with dichloromethane, washed with a 10% potassium carbonate aqueous solution, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 300: 1-100: 1) to obtain 134 mg of the title compound as a colorless solid (yield 92%).

    (31c) (2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9-[(pyridine- 2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-formic acid Ester    

(2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 31 (31b) was used -2,3,4,5,7,8,9,10-Octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and pyridine-2-carboxaldehyde The reaction was carried out in the same manner as the method described in Example 26 (26a) to obtain the title compound as a colorless solid (yield 76%).

    (31d) (2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9-[(pyridine- 2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 31 (31c) was used -9-[(pyridin-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] iso Methyl quinoline-8-formate was reacted in the same manner as in the method described in Example 25 (25i) to obtain the title compound (quantitative) as a colorless solid.

    (31e) N-{(2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- [ (Pyridine-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 31 (31d) was used -9-[(pyridin-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] iso Quinoline-8-formic acid was reacted in the same manner as in the method described in Example 25 (25j) to obtain the title compound as a colorless solid (yield: 73%).

    (31f) N-{(2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- [ (Pyridine-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-{(2S, 8S) -2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 obtained in Example 31 (31e) -Methyl-9-[(pyridin-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7- g] Isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was carried out in the same manner as the method described in Example 25 (25k). The reaction gave the title compound as a colorless solid (yield 78%).

    Example 32    

N-{(2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl} -9- [ (3-fluorophenyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] Isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (32a) (2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl) -4-methyl -3,4,5,7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary 8-methyl ester    

Using (S)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methanol obtained in Reference Example 15 (15c), the reaction was carried out in the same manner as in the method described in Example 31 (31a). The title compound was obtained as a colorless oily substance (yield 67%).

    (32b) (2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl) -4-methyl Methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] obtained in Example 32 (32a) was used Phenyl} -4-methyl-3,4,5,7,8,10-hexahydro [1,4] oxazepine [6,7-g] isoquinoline-8,9 (2H)- 9-Tributyl 8-methyl diformate was reacted in the same manner as in the method described in Example 31 (31b) to obtain the title compound as a colorless solid (yield: 94%).

    (32c) (2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl) -9- [ (3-fluorophenyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] Methyl isoquinoline-8-formate    

(2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] obtained in Example 32 (32b) was used Phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid The methyl ester and 3-fluorobenzaldehyde were reacted in the same manner as in the method described in Example 26 (26a) to obtain the title compound as a colorless solid (yield: 50%).

    (32d) (2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl) -9- [ (3-fluorophenyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] Isoquinoline-8-carboxylic acid    

(2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] obtained in Example 32 (32c) was used Phenyl} -9-[(3-fluorophenyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] Isoquinoline-8-carboxylic acid methyl ester was reacted in the same manner as the method described in Example 25 (25i) to obtain the title compound as a colorless solid (yield: 79%).

    (32e) N-{(2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl}- 9- (3-fluorobenzyl) -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] iso Quinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] obtained in Example 32 (32d) was used Phenyl} -9-[(3-fluorophenyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid was reacted in the same manner as the method described in Example 25 (25j) to obtain the title compound as a colorless solid (yield: 73%).

    (32f) N-{(2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl}- 9-[(3-fluorophenyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7 -g] isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-{[((2S, 8S) -2- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) obtained in Example 32 (32e) Methoxy] phenyl} -9-[(3-fluorophenyl) methyl] -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] Oxacridine [6,7-g] isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 25 The method described in (25k) was reacted in the same manner to obtain the title compound as a colorless solid (yield 75%).

    Example 33    

N-{(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[(3 -Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl } -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (33a) (2S, 8S) -4-Ethyl-2- (4-hydroxyphenyl) -3,4,5,7,8,10-hexahydro [1,4] oxyazepine [6 , 7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl 8-methyl ester    

(2S, 8S) -2- (4-hydroxyphenyl) -3,4,5,7,8,10-hexahydro [1,4] oxyazepine [13] obtained in Reference Example 13 (13p) [ To a solution of 6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tert-butyl 8-methyl ester (700 mg, 1.54 mmol) in dichloromethane (15 mL) was added pyridine (124 μL). , 1.54 mmol) and acetic anhydride (145 μL, 1.54 mmol), and stirred at room temperature for 10 minutes. The reaction solution was diluted with dichloromethane, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1-1: 2) to obtain 706 mg of the title compound as a colorless solid (yield 92%).

    (33b) (2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -3,4,5 , 7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tert-butyl 8-methyl ester    

(2S, 8S) -4-Ethyl-2- (4-hydroxyphenyl) -3,4,5,7,8,10-hexahydro [1,4 ] Oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary-butyl 8-methyl ester and (1S) -1- (4) obtained in Reference Example 4 3,4-Dichlorophenyl) propane-1-ol was reacted in the same manner as in the method described in Example 31 (31a) to obtain the title compound as a colorless solid (yield: 88%).

    (33c) (2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 33 (33b) was used } -3,4,5,7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl The methyl 8-methyl ester was reacted in the same manner as the method described in Example 31 (31b) to obtain the title compound as a colorless solid (yield: 99%).

    (33d) (2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[(3 -Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid Methyl ester    

(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 33 (33c) was used } -2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and 3-fluorobenzene Formaldehyde was reacted in the same manner as in the method described in Example 26 (26a) to obtain the title compound as a colorless solid (yield: 85%).

    (33e) (2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[(3 -Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 33 (33d) was used } -9-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] Methyl isoquinoline-8-formate was reacted in the same manner as in the method described in Example 25 (25i) to obtain the title compound (quantitative) as a colorless solid.

    (33f) N-{(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- [(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- 8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 33 (33e) was used } -9-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] Isoquinoline-8-formic acid was reacted in the same manner as in the method described in Example 25 (25j) to obtain the title compound as a colorless solid (yield: 67%).

    (33g) N-{(((2S, 8S) -4-ethylfluorenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -9 -[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline -8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-{[((2S, 8S) -4-ethylfluorenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxylate) obtained in Example 33 (33f) Yl] phenyl} -9-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6, 7-g] isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, the same method as described in Example 25 (25k) The reaction was carried out in situ to obtain the title compound as a colorless solid (71% yield).

    Example 34    

N-{(2S, 8S) -4-ethenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[(3 -Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl } -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (34a) (2S, 8S) -4-ethenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -3,4,5 , 7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tert-butyl 8-methyl ester    

Using the 9-tertiarybutyl 8-methyl (2S, 8S) -4-ethylfluorenyl-2- (4-hydroxyphenyl) -3,4,5,7 obtained in Example 33 (33a), 8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylate and (1R) -1- obtained in Reference Example 5 (3,4-Dichlorophenyl) propane-1-ol was reacted in the same manner as in the method described in Example 31 (31a) to obtain the title compound as a colorless solid (yield: 83%).

    (34b) (2S, 8S) -4-ethenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -4-ethenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 34 (34a) was used } -3,4,5,7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl The methyl 8-methyl ester was reacted in the same manner as in the method described in Example 31 (31b) to obtain the title compound as a colorless solid (yield: 95%).

    (34c) (2S, 8S) -4-ethenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[(3 -Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid Methyl ester    

(2S, 8S) -4-ethenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 34 (34b) was used } -2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and 3-fluorobenzene Formaldehyde was reacted in the same manner as in the method described in Example 26 (26a) to obtain the title compound as a colorless solid (yield 74%).

    (34d) (2S, 8S) -4-ethenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9-[(3 -Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

The (2S, 8S) -4-ethenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl group obtained in Example 34 (34c) was used } -9-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] Isoquinoline-8-formic acid methyl ester was reacted in the same manner as in the method described in Example 25 (25i) to obtain the title compound as a colorless solid (yield: 92%).

    (34e) N-{(2S, 8S) -4-ethenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- [(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- 8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -4-ethenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 34 (34d) was used } -9-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] Isoquinoline-8-carboxylic acid was reacted in the same manner as in the method described in Example 25 (25j) to obtain the title compound as a colorless solid (yield: 81%).

    (34f) N-{(2S, 8S) -4-ethenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- [(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- 8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-{[((2S, 8S) -4-ethylfluorenyl-2- {4-[(1S) -1- (3,4-dichlorophenyl) propoxylate) obtained in Example 34 (34e) Yl] phenyl} -9-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6, 7-g] isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, the same method as described in Example 25 (25k) The reaction was carried out in situ to obtain the title compound as a colorless solid (yield 77%).

    Example 35    

N-[(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- (2, 2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (35a) (2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- (2, 2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Methyl formate    

The (2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 33 (33c) } -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester (23mg, 0.040mmol ) Dissolved in N, N-dimethylformamide (0.40mL), sodium bicarbonate (8mg, 0.10mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (14μL, 0.10mmol) were added. ) And stirred at room temperature for 16 hours. Further, sodium bicarbonate (8 mg, 0.10 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (14 µL, 0.10 mmol) were added, and the mixture was stirred at room temperature for 6 hours. After diluting with ethyl acetate, it was washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1-3: 2) to obtain 18 mg of the title compound as a colorless solid (yield: 67%).

    (35b) (2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- (2, 2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Formic acid    

The (2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl group obtained in Example 35 (35a) was used } -9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxyazepine [6,7-g ] Isoquinoline-8-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 25 (25i) to obtain the title compound as a colorless solid (yield: 98%).

    (35c) N-[(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline -8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 35 (35b) was used } -9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxyazepine [6,7-g ] Isoquinoline-8-carboxylic acid was reacted in the same manner as in the method described in Example 25 (25j) to obtain the title compound as a colorless solid (yield: 37%).

    (35d) N-[(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline -8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -4-ethylfluorenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy group obtained in Example 35 (35c) ] Phenyl} -9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6, 7-g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, same method as described in Example 25 (25k) The reaction was carried out in situ to obtain the title compound as a colorless solid (71% yield).

    Example 36    

N-[(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- (2- (Methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4 -(2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (36a) (2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- (2- (Methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 33 (33c) was used } -2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and 2-methyl Propionaldehyde was reacted in the same manner as in the method described in Example 26 (26a) to obtain the title compound as a colorless solid (yield 87%).

    (36b) (2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- (2- (Methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 36 (36a) was used } -9- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline Methyl-8-formate was reacted in the same manner as in the method described in Example 25 (25i) to obtain the title compound (quantitative) as a colorless solid.

    (36c) N-[(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl ] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

The (2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained using Example 36 (36b) was used. } -9- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline 8-Formic acid was reacted in the same manner as in the method described in Example 25 (25j) to obtain the title compound as a colorless solid (yield 84%).

    (36d) N-[(2S, 8S) -4-ethenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -9- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl ] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -4-ethylfluorenyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy group obtained in Example 36 (36c) ] Phenyl} -9- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] Isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 25 (25k). The title compound was obtained as a colorless solid (yield 90%).

    Example 37    

N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-ethyl-9-[(3- Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (37a) (2S, 8S) -4-ethyl-2- (4-hydroxyphenyl) -3,4,5,7,8,10-hexahydro [1,4] oxyazepine [6, 7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl 8-methyl ester    

(2S, 8S) -2- (4-hydroxyphenyl) -3,4,5,7,8,10-hexahydro [1,4] oxyacridine obtained from Reference Example 13 (13p) [ 6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tert-butyl 8-methyl ester and acetaldehyde were reacted in the same manner as described in Reference Example 13 (13q) to obtain The title compound as a colorless solid (63% yield).

    (37b) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-ethyl-3,4,5, 7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tert-butyl 8-methyl ester    

(2S, 8S) -4-ethyl-2- (4-hydroxyphenyl) -3,4,5,7,8,10-hexahydro [1,4] obtained in Example 37 (37a) was used Oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tert-butyl 8-methyl ester and (1S) -1- (3) obtained in Reference Example 4 , 4-Dichlorophenyl) propane-1-ol was reacted in the same manner as in the method described in Example 31 (31a) to obtain the title compound as a colorless solid (yield: 81%).

    (37c) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-ethyl-2,3,4, 5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-ethyl obtained in Example 37 (37b) was used -3,4,5,7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl 8-methyl ester was reacted in the same manner as the method described in Example 31 (31b) to obtain the title compound as a colorless solid (yield: 98%).

    (37d) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-ethyl-9-[(3- Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-formic acid Ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-ethyl obtained in Example 37 (37c) was used -2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and 3-fluorobenzaldehyde The reaction was carried out in the same manner as in the method described in Example 26 (26a) to obtain the title compound as a colorless solid (yield: 88%).

    (37e) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-ethyl-9-[(3- Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid    

Using (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl})-4-ethyl obtained in Example 37 (37d) -9-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxyazepine [6,7-g] Methyl isoquinoline-8-formate was reacted in the same manner as in the method described in Example 25 (25i) to obtain the title compound (quantitative) as a colorless solid.

    (37f) N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-ethyl-9- [ (3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-ethyl obtained in Example 37 (37e) was used -9-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] iso Quinoline-8-formic acid was reacted in the same manner as in the method described in Example 25 (25j) to obtain the title compound as a colorless solid (yield: 72%).

    (37g) N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-ethyl-9- [ (3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 obtained in Example 37 (37f) -Ethyl-9- (3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g ] Isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 25 (25k). The title compound was obtained as a colorless solid (yield 94%).

    Example 38    

N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- (2,2 , 2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl ] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (38a) (2S, 8S) -4- (2-nitrobenzene-1-sulfonyl) -2- {4-{[(2-nitrobenzene-1-sulfonyl) oxy] phenyl } -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -4- (2-nitrobenzene-1-sulfonyl) -2- {4-[(2-nitrobenzene-1-sulfonyl) obtained in Reference Example 13 (130) ) Oxy] phenyl} -3,4,5,7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -di Trifluoroacetic acid (2.1 mL) was added to a chloroform (3.2 mL) solution of 9-tert-butyl 8-methyl formate, and the mixture was stirred at room temperature for 30 minutes. After dilution with chloroform, a 10% potassium carbonate aqueous solution was added and neutralized. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 300: 1-200: 1) to obtain 534 mg of the title compound as a pale yellow solid (purity 84%, yield 96%).

    (38b) (2S, 8S) -4- (2-nitrobenzene-1-sulfonyl) -2- {4-[(2-nitrobenzene-1-sulfonyl) oxy] phenyl} -9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] Methyl isoquinoline-8-formate    

(2S, 8S) -4- (2-nitrobenzene-1-sulfonyl) -2- {4-{[(2-nitrobenzene-1-sulfonyl) obtained in Example 38 (38a) was used Yl) oxy] phenyl} -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid The methyl ester was reacted in the same manner as in the method described in Example 35 (35a) to obtain the title compound as a colorless solid (purity 89%, yield 72%).

    (38c) (2S, 8S) -2- (4-hydroxyphenyl) -9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10- Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -4- (2-nitrobenzene-1-sulfonyl) -2- {4-[(2-nitrobenzene-1-sulfonyl) obtained in Example 38 (38b) was used ) Oxy] phenyl} -9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxyazepine [6,7-g] Isoquinoline-8-carboxylic acid methyl ester was reacted in the same manner as described in Reference Example 13 (13p) to obtain the title compound as a colorless solid (yield: 80%).

    (38d) (2S, 8S) -2- (4-hydroxyphenyl) -4-methyl-9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8 , 9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- (4-hydroxyphenyl) -9- (2,2,2-trifluoroethyl) -2,3,4,5,7 obtained in Example 38 (38c) , 8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester was reacted in the same manner as the method described in Reference Example 13 (13q), The title compound was obtained as a colorless solid (94% yield).

    (38e) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- (2,2 , 2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid Methyl ester    

Using (2S, 8S) -2- (4-hydroxyphenyl) -4-methyl-9- (2,2,2-trifluoroethyl) -2,3, obtained in Example 38 (38d), 4,5,7,8,9,10-Octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and (1S)- 1- (3,4-dichlorophenyl) propane-1-ol was reacted in the same manner as in the method described in Example 31 (31a) to obtain the title compound as a colorless solid (yield 75%).

    (38f) methyl (2S, 8S) -2- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-methyl-9- (2 , 2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8 -Formic acid    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 38 (38e) was used -9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] Methyl isoquinoline-8-formate was reacted in the same manner as in the method described in Example 25 (25i) to obtain the title compound (quantitative) as a colorless solid.

    (38g) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- ( 2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- 8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 38 (38f) was used -9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] Isoquinoline-8-carboxylic acid was reacted in the same manner as in the method described in Example 25 (25j) to obtain the title compound as a colorless solid (yield 71%).

    (38h) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- ( 2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- 8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 obtained in Example 38 (38 g) -Methyl-9- (2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7 -g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, the same method as described in Example 25 (25k) The reaction was performed to obtain the title compound as a colorless solid (yield 91%).

    Example 39    

N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- (2-methyl Propyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine

    (39a) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-methyl-3,4,5, 7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tert-butyl 8-methyl ester    

(2S, 8S) -2- (4-hydroxyphenyl) -4-methyl-3,4,5,7,8,10-hexahydro [1,4] obtained in Reference Example 13 (13q) Oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl 8-methyl ester (400 mg, 0.854 mmol) and (1S obtained in Reference Example 4 ) -1- (3,4-dichlorophenyl) propane-1-ol (263 mg, 1.28 mmol) in toluene (5.6 mL) was added with tri-n-butylphosphine (319 μL, 1.28 mmol), 1, After 1'-azobis (N, N-dimethylformamidine) (220 mg, 1.28 mmol), it was stirred at 40 ° C for 1.5 hours. The reaction solution was left to cool to room temperature, and insoluble matters were filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1-2: 3) to obtain 465 mg of the title compound as a colorless solid (yield: 83%).

    (39b) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-methyl-2,3,4, 5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}-obtained in Example 39 (39a) under a nitrogen atmosphere 4-methyl-3,4,5,7,8,10-hexahydro [1,4] oxazepine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9- In a solution of tertiary butyl 8-methyl ester (465 mg, 0.709 mmol) in dichloromethane (7.1 mL), under ice cooling, trimethylsilyl iodide (252 μL, 1.77 mmol) was added and stirred at the same temperature for 10 minutes. minute. The reaction solution was diluted with dichloromethane, washed with a 10% potassium carbonate aqueous solution, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 372 mg of the title compound as a colorless solid (yield: 94%).

    (39c) (2S, 8S) -2- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-methyl-9- (2-methyl Propyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 39 (39b) -2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester (172mg, 0.310mmol) To a solution of isobutyl aldehyde (70 μL, 0.7774 mmol) in dichloromethane (2 mL), acetic acid (18 μL, 0.310 mmol) and sodium triacetoxyborohydride (197 mg, 0.929 mmol) were added and stirred for 2 hours. The reaction solution was diluted with dichloromethane, washed with a saturated sodium bicarbonate aqueous solution, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1-1: 1) to obtain 160 mg of the title compound (yield: 85%) as a colorless solid.

    (39d) (2S, 8S) -2- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-methyl-9- (2-methyl Propyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 39 (39c) -9- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- To a solution of methyl 8-formate (160 mg, 0.262 mmol) in tetrahydrofuran (2.6 mL) / methanol (1.3 mL), a 1N-sodium hydroxide aqueous solution (0.65 mL, 0.65 mmol) was added, and the mixture was stirred at room temperature for 16 hours. 1N-hydrochloric acid was added to the reaction solution and the pH was adjusted to 4-5. Then, the mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 157 mg of the title compound (quantitative) as a colorless solid. .

    (39e) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- ( 2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 39 (39d) -9- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- 8-formic acid (157 mg, 0.263 mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methane sulfonate (140 mg, 0.368 mmol) obtained in Reference Example 31 ) In N, N-dimethylformamide (3.2 mL) solution, N, N-diisopropylethylamine (135 μL, 0.788 mmol), O- (azabenzimidazole) were added at room temperature. 1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (140 mg, 0.368 mmol), and stirred for 5 hours. Water was added to the reaction solution, and the suspension was collected by filtration and washed with diisopropyl ether. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 300: 1-50: 1) to obtain 166 mg of the title compound as a colorless solid (yield: 73%).

    (39f) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- ( 2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 obtained in Example 39 (39e) -Methyl-9- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] iso Quinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (166 mg, 0.192 mmol) in tetrahydrofuran (1.3 mL) / methanol (0.4 mL ) To the solution, a 1N-sodium hydroxide aqueous solution (0.42 mL, 0.423 mmol) was added, and the mixture was stirred at room temperature for 2 hours. 1N-hydrochloric acid was added to the reaction solution to adjust the pH to 4-5, and the organic solvent was distilled off under reduced pressure. Water was added to the residue, and the precipitate was collected by filtration and dried to obtain 136 mg of the title compound as a colorless solid (yield: 83%).

    Example 40    

N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- (propane-2 -Yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- ( 2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (40a) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- (propane-2 -Yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 39 (39b) was used -2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and acetone, and examples The method described in 39 (39c) was similarly reacted to obtain the title compound as a colorless solid (yield: 82%).

    (40b) (2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -4-methyl-9- (propane-2 -Yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 40 (40a) was used -9- (propane-2-yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8 -Methyl formate, which was reacted in the same manner as described in Example 39 (39d) to obtain the title compound (quantitative) as a colorless solid.

    (40c) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- ( Propane-2-yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl]- 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 40 (40b) was used -9- (propane-2-yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8 -Formic acid was reacted in the same manner as in the method described in Example 39 (39e) to obtain the title compound as a colorless solid (yield 65%).

    (40d) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-9- ( Propane-2-yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl]- 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4 obtained in Example 40 (40c) -Methyl-9- (propane-2-yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquine Phenolin-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as described in Example 39 (39f) to obtain The title compound as a colorless solid (82% yield).

    Example 41    

N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl-9- (2-methyl Propyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine

    (41a) (2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl) -4-methyl-3,4,5, 7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tert-butyl 8-methyl ester    

(1S) -1- (3,4-difluorophenyl) propane-1-ol obtained in Reference Example 6 was reacted in the same manner as in the method described in Example 39 (39a) to obtain the title of a colorless solid. Compound (83% yield).

    (41b) (2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl) -4-methyl-2,3,4, 5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl obtained in Example 41 (41a) was used -3,4,5,7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary butyl 8-methyl ester was reacted in the same manner as in the method described in Example 39 (39b) to obtain the title compound (quantitative) as a colorless solid.

    (41c) (2S, 8S) -2- (4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl) -4-methyl-9- (2-methyl Propyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl obtained in Example 41 (41b) was used -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and isobutylaldehyde, The reaction was carried out in the same manner as the method described in Example 39 (39c) to obtain the title compound as a colorless solid (yield: 78%).

    (41d) (2S, 8S) -2- (4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl) -4-methyl-9- (2-methyl Propyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl obtained in Example 41 (41c) was used -9- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- Methyl 8-formate was reacted in the same manner as in the method described in Example 39 (39d) to obtain the title compound as a colorless solid (yield: 97%).

    (41e) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl-9- ( 2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl obtained in Example 41 (41d) was used -9- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- 8-formic acid was reacted in the same manner as in the method described in Example 39 (39e) to obtain the title compound as a colorless solid (yield: 55%).

    (41f) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl-9- ( 2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4 obtained in Example 41 (41e) -Methyl-9- (2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] iso Quinoline-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 39 (39f) to obtain The title compound was obtained as a colorless solid (83% yield).

    Example 42    

N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl-9- (propane-2 -Yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- ( 2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (42a) (2S, 8S) -2- (4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl) -4-methyl-9- (propane-2 -Yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl obtained in Example 41 (41b) was used -2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and acetone, and examples The method described in 39 (39c) was similarly reacted to obtain the title compound as a colorless solid (yield: 78%).

    (42b) (2S, 8S) -2- (4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl) -4-methyl-9- (propane-2 -Yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl- obtained in Example 42 (42a) 9- (propane-2-yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Methyl formate was reacted in the same manner as the method described in Example 39 (39d) to obtain the title compound (quantitative) as a colorless solid.

    (42c) N-[(2S, 8S) -2- (4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl) -4-methyl-9- ( Propane-2-yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl]- 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl obtained in Example 42 (42b) was used -9- (propane-2-yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8 -Formic acid was reacted in the same manner as the method described in Example 39 (39e) to obtain the title compound as a colorless solid (yield: 62%).

    (42d) N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl-9- ( Propane-2-yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl]- 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4 obtained in Example 42 (42c) -Methyl-9- (propane-2-yl) -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquine Phenolin-8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as described in Example 39 (39f) to obtain The title compound as a colorless solid (81% yield).

    Example 43    

N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl-9-[(3- Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (43a) (2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl-9-[(3- Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-formic acid Ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl obtained in Example 41 (41b) was used -2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and 3-fluorobenzaldehyde The reaction was carried out in the same manner as in the method described in Example 39 (39c) to obtain the title compound as a colorless solid (yield: 87%).

    (43b) (2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl-9-[(3- Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl obtained in Example 43 (43a) was used -9-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] iso Methyl quinoline-8-formate was reacted in the same manner as in the method described in Example 39 (39d) to obtain the title compound as a colorless solid (yield: 97%).

    (43c) N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl-9- [ (3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl obtained in Example 43 (43b) was used -9-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] iso Quinoline-8-formic acid was reacted in the same manner as in the method described in Example 39 (39e) to obtain the title compound as a colorless solid (yield: 70%).

    (43d) N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4-methyl-9- [ (3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8 -Carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-{(2S, 8S) -2- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -4 obtained in Example 43 (43c) -Methyl-9-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7- g] Isoquinoline-8-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was carried out in the same manner as the method described in Example 39 (39f). The reaction gave the title compound as a colorless solid (88% yield).

    Example 44    

N-[(2S, 8S) -9-cyclopentyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl- 2,3,4,5,7,8,9,10-Octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3- (Dimethylpyridin-4-yl) -L-phenylalanine

    (44a) (2S, 8S) -9-cyclopentyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl- 2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 39 (39b) -2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester (400mg, 0.720mmol) To a solution of cyclopentanone (191 μL, 2.16 mmol) in dichloromethane (14.4 mL), acetic acid (124 μL, 2.16 mmol) and sodium triacetoxyborohydride (610 mg, 2.88 mmol) were added and stirred for 18 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the organic layer was separated. After the aqueous layer was extracted with dichloromethane, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15-65: 35) to obtain 404 mg of the title compound (yield 90%) as a white amorphous substance.

    (44b) (2S, 8S) -9-cyclopentyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl- 2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -9-cyclopentyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 44 (44a) } -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester (403 mg, 0.646 mmol) in a methanol (6.5 mL) / tetrahydrofuran (6.5 mL) solution, a solution of lithium hydroxide monohydrate (542 mg, 12.9 mmol) in water (6.5 mL) was added, and the mixture was stirred at 50 ° C. for 3 hours. After the reaction solution was allowed to cool to room temperature, 1N-hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH to around 7.0, and then the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 400 mg of the title compound (quantitative) as a pale yellow solid.

    (44c) N-[(2S, 8S) -9-cyclopentyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4- Methyl-2,3,4,5,7,8,9,10-Octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2 , 3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -9-cyclopentyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 44 (44b) } -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid (393mg N, methyl 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methanesulfonate (294 mg, 0.773 mmol) obtained in Reference Example 31, To a solution of N-dimethylformamide (6.5 mL), triethylamine (268 μL, 1.93 mmol) was added and stirred. Secondly, 4- (4,6-dimethoxy-1,3,5-trichloro -2-yl) -4-methyl Porphyrinium (247 mg, 0.838 mmol) and stirred at room temperature for 2 hours. Water was added to the reaction solution, and extraction was performed twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 0-95: 5) to obtain 585 mg of the title compound (quantitative) as a pale yellow amorphous substance.

    (44d) N-[(2S, 8S) -9-cyclopentyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4- Methyl-2,3,4,5,7,8,9,10-Octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2 , 3-Dimethylpyridin-4-yl) -L-phenylalanine    

N-[(2S, 8S) -9-cyclopentyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 44 (44c) ] Phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (564 mg, 0.644 mmol) in a solution of methanol (6.4 mL) / tetrahydrofuran (6.4 mL), added A solution of lithium hydroxide monohydrate (540 mg, 12.9 mmol) in water (6.4 mL) was stirred at room temperature for 2 hours. 1N-hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, the pH was adjusted to around 6.0, and then the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 90: 10-85: 15-70: 30) to obtain 248 mg of the title compound as a white solid (yield 45%).

    Example 45    

N-[(2S, 8S) -9- (cyclobutylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2, 3-dimethylpyridin-4-yl) -L-phenylalanine

    (45a) (2S, 8S) -9- (cyclobutylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl Methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 39 (39b) was used -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and cyclobutanecarboxaldehyde, The reaction was carried out in the same manner as in the method described in Example 44 (44a) to obtain the title compound (yield: 83%) as a white amorphous substance.

    (45b) (2S, 8S) -9- (cyclobutylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -9- (cyclobutylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] obtained in Example 45 (45a) was used Phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid The methyl ester was reacted in the same manner as described in Example 44 (44b) to obtain the title compound (quantitative) as a pale yellow solid.

    (45c) N-[(2S, 8S) -9- (cyclobutylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}- 4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -9- (cyclobutylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] obtained in Example 45 (45b) was used Phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid The reaction was carried out in the same manner as in the method described in Example 44 (44c) to obtain the title compound (yield 67%) as a pale yellow amorphous substance.

    (45d) N-[(2S, 8S) -9- (cyclobutylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}- 4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -9- (cyclobutylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propane obtained in Example 45 (45c) Oxy] phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline- 8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 44 (44d) to obtain a white solid. The title compound (43% yield).

    Example 46    

N-[(2S, 8S) -9- (cyclohexylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4- Methyl-2,3,4,5,7,8,9,10-Octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2 , 3-Dimethylpyridin-4-yl) -L-phenylalanine

    (46a) (2S, 8S) -9- (cyclohexylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4- Methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 39 (39b) was used -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and cyclohexane formaldehyde, The reaction was carried out in the same manner as the method described in Example 44 (44a) to obtain the title compound (yield: 92%) as a white amorphous substance.

    (46b) (2S, 8S) -9- (cyclohexylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4- Methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -9- (cyclohexylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 46 (46a) was used ] Phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Methyl formate was reacted in the same manner as the method described in Example 44 (44b) to obtain the title compound (quantitative) as a pale yellow solid.

    (46c) N-[(2S, 8S) -9- (cyclohexylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4 -(2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -9- (cyclohexylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 46 (46b) was used ] Phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Formic acid was reacted in the same manner as in the method described in Example 44 (44c) to obtain the title compound as a pale yellow amorphous substance (yield: 79%).

    (46d) N-[(2S, 8S) -9- (cyclohexylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4 -(2,3-dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -9- (cyclohexylmethyl) -2- {4-[(1R) -1- (3,4-dichlorophenyl) obtained in Example 46 (46c) Propoxy] phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline -8-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 44 (44d) to obtain a white color. The title compound as a solid (65% yield).

    Example 47    

N-[(2S, 8S) -9-cyclobutyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl- 2,3,4,5,7,8,9,10-Octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3- (Dimethylpyridin-4-yl) -L-phenylalanine

    (47a) (2S, 8S) -9-cyclobutyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl- 2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 39 (39b) was used -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and cyclobutanone, and The reaction was carried out in the same manner as in Example 44 (44a) to obtain the title compound (yield: 83%) as a white amorphous substance.

    (47b) (2S, 8S) -9-cyclobutyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl- 2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -9-cyclobutyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 47 (47a) was used } -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid methyl ester The reaction was carried out in the same manner as in the method described in Example 44 (44b) to obtain the title compound (quantitative) as a pale yellow solid.

    (47c) N-[(2S, 8S) -9-cyclobutyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4- Methyl-2,3,4,5,7,8,9,10-Octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2 , 3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -9-cyclobutyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 47 (47b) was used } -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid, and The reaction was carried out in the same manner as described in Example 44 (44c) to obtain the title compound (yield 76%) as a light brown amorphous substance.

    (47d) N-[(2S, 8S) -9-cyclobutyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4- Methyl-2,3,4,5,7,8,9,10-Octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2 , 3-Dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -9-cyclobutyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 47 (47c) ] Phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8- Carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as described in Example 44 (44d) to obtain the title as a white solid. Compound (52% yield).

    Example 48    

N-[(2S, 8S) -9-cyclohexyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-2 , 3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-di (Methylpyridin-4-yl) -L-phenylalanine

    (48a) (2S, 8S) -9-cyclohexyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-2 , 3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl obtained in Example 39 (39b) -2,3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester (400mg, 0.720mmol) To a solution of cyclohexanone (223 μL, 2.16 mmol) in dichloromethane (14.4 mL), acetic acid (124 μL, 2.16 mmol) and sodium triacetoxyborohydride (610 mg, 2.88 mmol) were added and stirred for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic layer was separated. After the aqueous layer was extracted with dichloromethane, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25-0: 100) to obtain 402 mg of the title compound as a white amorphous substance (yield 88%).

    (48b) (2S, 8S) -9-cyclohexyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl-2 , 3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

(2S, 8S) -9-cyclohexyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) obtained in Example 48 (48a) 4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid methyl ester ( A solution of 402 mg, 0.631 mmol) in methanol (6.3 mL) / tetrahydrofuran (6.3 mL) was added with a solution of lithium hydroxide monohydrate (530 mg, 12.6 mmol) in water (6.3 mL), and the mixture was stirred at 50 ° C. for 3 hours. After the reaction solution was allowed to cool to room temperature, 1N-hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH to around 7.0, and then the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 402 mg of the title compound (quantitative) as a pale yellow solid.

    (48c) N-[(2S, 8S) -9-cyclohexyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2, 3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -9-cyclohexyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} obtained in Example 48 (48b) 4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid (401mg, 0.643 mmol) and N-N- of 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methane sulfonate (302 mg, 0.772 mmol) obtained in Reference Example 31 To a solution of dimethylformamide (6.6 mL), N, N, -diisopropylethylamine (340 μL, 1.93 mmol) was added and stirred. Next, add O- (7-azabenzimidazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (352 mg, 0.900 mmol) and stir at room temperature 3 hours. Water was added to the reaction solution, and extraction was performed twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 0-85: 15) to obtain 452 mg of the title compound as a light brown amorphous substance (yield 79%).

    (48d) N-[(2S, 8S) -9-cyclohexyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -4-methyl -2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2, 3-dimethylpyridin-4-yl) -L-phenylalanine    

N-[(2S, 8S) -9-cyclohexyl-2- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy]] obtained in Example 48 (48c) Phenyl} -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl ] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (452 mg, 0.508 mmol) in methanol (5.1 mL) / tetrahydrofuran (5.1 mL) solution, hydrogen was added A solution of lithium oxide monohydrate (426 mg, 10.1 mmol) in water (5.1 mL) was stirred at room temperature for 2 hours. 1N-hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the pH was adjusted to around 6.0, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 0-70: 30) to obtain 271 mg of the title compound as a white solid (yield 61%).

    Example 49    

N-[(2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -4-methyl-2, 3,4,5,7,8,9,10-Octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3-dimethyl Pyridin-4-yl) -L-phenylalanine

    (49a) (2S, 8S) -2- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -4-methyl-3,4,5,7,8,10- Hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tert-butyl 8-methyl ester    

Using 3,4- (dichlorophenyl) methanol, a reaction was carried out in the same manner as in the method described in Example 39 (39a) to obtain the title compound (yield: 70%) as a white amorphous substance.

    (49b) (2S, 8S) -2- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -4-methyl-2,3,4,5,7,8, 9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -4-methyl-3,4,5 obtained in Example 49 (49a) was used , 7,8,10-hexahydro [1,4] oxacridine [6,7-g] isoquinoline-8,9 (2H) -dicarboxylic acid 9-tertiary-butyl 8-methyl ester, The reaction was carried out in the same manner as in the method described in Example 39 (39b) to obtain the title compound (yield: 99%) as a short yellow solid.

    (49c) (2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -4-methyl-2, 3,4,5,7,8,9,10-Octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester    

(2S, 8S) -2- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -4-methyl-2,3,4 obtained in Example 49 (49b) was used , 5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid methyl ester and cyclopentanecarboxaldehyde, and Example 44 (44a The method described in) was carried out in the same manner to obtain the title compound (yield 87%) as a white amorphous substance.

    (49d) (2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -4-methyl-2, 3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid    

Example 49 (49c) (2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -4-methyl Methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carboxylic acid methyl ester, and Example 44 The method described in (44b) was performed in the same manner to obtain the title compound (quantitative) as a pale yellow solid.

    (49e) N-[(2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -4-methyl -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3 -Dimethylpyridin-4-yl) -L-phenylalanine methyl ester    

(2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(3,4-dichlorophenyl) methoxy] phenyl}-obtained in Example 49 (49d) was used 4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carboxylic acid, and the examples The method described in 44 (44c) was performed in the same manner to obtain the title compound (yield 91%) as a pale yellow amorphous substance.

    (49f) N-[(2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -4-methyl -2,3,4,5,7,8,9,10-octahydro [1,4] oxacridine [6,7-g] isoquinoline-8-carbonyl] -4- (2,3 -Dimethylpyridin-4-yl) -L-phenylalanine    

Using N-[(2S, 8S) -9- (cyclopentylmethyl) -2- {4-[(3,4-dichlorophenyl) methoxy] benzene obtained in Example 49 (49e) } -4-methyl-2,3,4,5,7,8,9,10-octahydro [1,4] oxazepine [6,7-g] isoquinoline-8-carbonyl] 4- (2,3-Dimethylpyridin-4-yl) -L-phenylalanine methyl ester was reacted in the same manner as the method described in Example 44 (44d) to obtain the title compound as a white solid ( Yield: 47%).

    Example 50    

N-[(4S, 9S) -8-cyclopentyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7,8 , 9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(50a) (4S, 9S) -8-cyclopentyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7,8 , 9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7, obtained in Reference Example 20 (20b), 8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (250 mg, 0.488 mmol) and cyclopentanone (87 μL, 0.976 mmol) in dichloromethane (3.25 mL), and acetic acid ( 28 μL, 0.488 mmol), sodium triacetoxyborohydride (310 mg, 1.46 mmol), and stirred at room temperature for 3 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 → 80/20) to obtain 264 mg of the title compound as a white solid (93% yield).

(50b) (4S, 9S) -8-cyclopentyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7,8 , 9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -8-cyclopentyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3, obtained in Example 50 (50a), 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (264mg, 0.455mmol) in a solution of tetrahydrofuran (4.55mL) / methanol (2.27mL), add 2N-sodium hydroxide aqueous solution under ice cooling (2.27 mL, 4.55 mmol) and stirred at room temperature for 16 hours. 2N-hydrochloric acid (2.27mL, 4.55mmoL) was added to the reaction solution, and the solution was extracted with dichloromethane (× 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title of 251mg as a white solid Compound (yield 97%).

(50c) N-{[((4S, 9S) -8-cyclopentyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl) -2,3,4,5 , 7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinolin-9-yl] carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -8-cyclopentyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl}-obtained in Example 50 (50b) under a nitrogen atmosphere 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid (251 mg, 0.443 mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenyl obtained in Reference Example 31 To a solution of methyl alanine methane sulfonate (202 mg, 0.532 mmol) in N, N-dimethylformamidine (4.43 mL), under ice cooling, add O- (azabenzimidazole-1) sequentially -Yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (219 mg, 0.576 mmol), N, N-diisopropylethylamine (232 μL, 1.33 mmol), under ice cooling , Stirred for 1 hour, and then stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with water and saturated brine in this order, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 → 30/70) to obtain 259 mg of the title compound as a white amorphous substance (yield: 70). %).

(50d) N-[(4S, 9S) -8-cyclopentyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5, 7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

N-{[((4S, 9S) -8-cyclopentyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl)}-obtained in Example 50 (50c) 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (259mg, 0.311mmol) In a solution of tetrahydrofuran (3.11 mL) / methanol (1.55 mL), 2N-sodium hydroxide aqueous solution (1.55 mL, 3.11 mmol) was added under ice-cooling, and the solution was stirred under ice-cooling for 0.5 hours, and then stirred at room temperature for 1 hour. 2N-hydrochloric acid (1.55mL, 3.11mmol) was added to the reaction solution, and the mixture was extracted with dichloromethane / methanol = 9/1 (× 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 255 mg of the title compound (quantitative) as a white amorphous substance.

    Example 51    

2-chloro-N-{(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(51a) (9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -2,3,4,5, obtained in Reference Example 22 (22b), 7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester -3-Formaldehyde was reacted in the same manner as in the method described in Example 50 (50a) to obtain the title compound as a colorless solid (yield 87%).

(51b) (9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -8-[(Da -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound as a colorless solid (yield 96%).

(51c) 2-chloro-N-{[(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

((9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -8-[(Da -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 2-chloro-4- (2,3-dimethylpyridin-4-yl) -L-benzene obtained in Reference Example 32 (32d) The methyl alanine dihydrochloride was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a light brown solid (yield 44%).

(51d) 2-chloro-N-{(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using 2-chloro-N-{(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] -3-fluorophenyl} -8 obtained in Example 51 (51c) -[(despair -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound as a light brown solid (yield 61%).

    Example 52    

2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) ethoxy] phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(52a) (9S) -4- {4- [1- (3,4-dichlorophenyl) ethoxy] phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4- [1- [3,4-dichlorophenyl) ethoxy] phenyl} -2,3,4,5,7, obtained in Reference Example 23 (23b), 8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester -3-Formaldehyde was reacted in the same manner as in the method described in Example 50 (50a) to obtain the title compound as a colorless solid (yield 75%).

(52b) (9S) -4- {4- [1- (3,4-dichlorophenyl) ethoxy] phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(9S) -4- {4- [1- (3,4-dichlorophenyl) ethoxy] phenyl} -8-[(Da -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound as a colorless solid (yield 84%).

(52c) 2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) ethoxy] phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(9S) -4- {4- [1- [3,4-dichlorophenyl) ethoxy] phenyl} -8-[(Da -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 2-chloro-4- (2,3-dimethylpyridin-4-yl) -L-benzene obtained in Reference Example 32 (32d) The methyl alanine dihydrochloride was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a light brown solid (yield 51%).

(52d) 2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) ethoxy] phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using 2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) ethoxy] phenyl} -8- [obtained in Example 52 (52c) (despair -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound as a light brown solid (yield: 51%).

    Example 53    

2-chloro-N-{(9S) -4- {4- (cyclohexylmethoxy) phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(53a) (9S) -4- [4- (cyclohexylmethoxy) phenyl] -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- [4- (cyclohexylmethoxy) phenyl] -2,3,4,5,7,8,9,10-octahydro obtained in Reference Example 24 (24b) 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester -3-Formaldehyde was reacted in the same manner as in the method described in Example 50 (50a) to obtain the title compound as a colorless solid (yield: 79%).

(53b) (9S) -4- [4- (cyclohexylmethoxy) phenyl] -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(9S) -4- [4- (cyclohexylmethoxy) phenyl] -8-[(Da -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound as a colorless solid (yield: 83%).

(53c) 2-chloro-N-((9S) -4- (cyclohexylmethoxy) phenyl) -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(9S) -4- [4- (cyclohexylmethoxy) phenyl] -8-[(Da -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 2-chloro-4- (2,3-dimethylpyridin-4-yl) -L-benzene obtained in Reference Example 32 (32d) The methyl alanine dihydrochloride was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a light brown solid (yield 51%).

(53d) 2-chloro-N-{(9S) -4- {4- (cyclohexylmethoxy) phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using 2-chloro-N-{(9S) -4- (cyclohexylmethoxy) phenyl) obtained from Example 53 (53c)}-8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was conducted in the same manner to obtain the title compound as a light brown solid (yield: 63%).

    Example 54    

2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(pyridin-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(54a) (9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(pyridin-2-yl) methyl] -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4- [1- [3,4-dichlorophenyl) propoxy] phenyl} -2,3,4,5,7, obtained in Reference Example 25 (25b), 8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and pyridine-2-carboxaldehyde were reacted in the same manner as described in Example 50 (50a) to obtain the title compound as a colorless solid (yield 85%).

(54b) (9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(pyridin-2-yl) methyl] -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(9S) -4- {4- [1- [3,4-dichlorophenyl) propoxy] phenyl} -8-[(pyridin-2-yl) obtained in Example 54 (54a) was used (Methyl) -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound (quantitative) as a colorless solid.

(54c) 2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(pyridin-2-yl) (Methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(9S) -4- {4- [1- [3,4-dichlorophenyl) propoxy] phenyl} -8-[(pyridin-2-yl) obtained in Example 54 (54b) was used (Methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 2-chloro-4- (2,3-dimethylpyridin-4-yl) -L-benzene obtained in Reference Example 32 (32d) The methyl alanine dihydrochloride was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a light brown solid (yield 56%).

(54d) 2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(pyridin-2-yl) (Methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

2-chloro-N-{[(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8- [obtained in Example 54 (54c) (Pyridin-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was conducted in the same manner to obtain the title compound as a light brown solid (yield 87%).

    Example 55    

2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(55a) (9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4- [1- [3,4-dichlorophenyl) propoxy] phenyl} -2,3,4,5,7, obtained in Reference Example 25 (25b), 8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester -3-Formaldehyde was reacted in the same manner as described in Example 50 (50a) to obtain the title compound as a colorless solid (yield: 85%).

(55b) (9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(9S) -4- {4- [1- [3,4-dichlorophenyl) propoxy] phenyl} -8-[(Da -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound as a colorless solid (yield: 92%).

(55c) 2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(9S) -4- {4- [1- [3,4-dichlorophenyl) propoxy] phenyl} -8-[(Da -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 2-chloro-4- (2,3-dimethylpyridin-4-yl) -L-benzene obtained in Reference Example 32 (32d) The methyl alanine dihydrochloride was reacted in the same manner as the method described in Example 50 (50c) to obtain the title compound (yield: 47%) as a light brown solid.

(55d) 2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[( -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using 2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8- [obtained in Example 55 (55c) (despair -3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was conducted in the same manner to obtain the title compound as a light brown solid (yield 67%).

    Example 56    

N-{(9S) -4- {4-[(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl} -8-[(5-methyl- 1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(56a) (9S) -4- {4-[(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl} -8-[(5-methyl- 1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4-[(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl} -2 obtained in Reference Example 27 (27b), 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester and 5-methyl-1,2- The azole-3-carbaldehyde was reacted in the same manner as in the method described in Example 50 (50a) to obtain the title compound (yield 94%) as a white amorphous substance.

(56b) (9S) -4- {4-[(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl) -8-[(5-methyl- 1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(9S) -4- {4-[(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl} -8- obtained in Example 56 (56a) was used [(5-methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as described in Example 50 (50b) to obtain the title compound (quantitative) as a white solid.

(56c) N-{(9S) -4- {4-[(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl) -8-[(5- Methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(9S) -4- {4-[(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl} -8- obtained in Example 56 (56b) was used. [(5-methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound (yield 57%) as a pale yellow amorphous substance.

(56d) N-{(9S) -4- {4-[(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl} -8-[(5- Methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-{(9S) -4- {4-[(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl) obtained in Example 56 (56c) -8-[(5-methyl-1,2- Azol-3-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was performed in the same manner to obtain the title compound as a white solid (yield: 95%).

    Example 57    

N-{(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(3-fluorophenyl) methyl Radical) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(57a) (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(3-fluorophenyl) formaldehyde Radical) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

Using (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28b), 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-formic acid methyl ester and 3-fluorobenzaldehyde were reacted in the same manner as described in Example 50 (50a) to obtain the title of a white amorphous substance Compound (90% yield).

(57b) (4S, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8-[(3-fluorophenyl) methyl Radical) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[( 3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as described in Example 50 (50b) to obtain the title compound (quantitative) as a white solid.

(57c) N-{(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(3-fluorobenzene (Methyl) methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinolin-9-yl] carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[( 3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound (yield: 58%) as a white amorphous substance.

(57d) N-{(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-[(3-fluorobenzene (Methyl) methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-{(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8 obtained in Example 57 (57c) -[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was conducted in the same manner to obtain the title compound as a white solid (yield: 92%).

    Example 58    

N-{(4S, 9S) -4- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl} -8- [ (3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(58a) (4S, 9S) -4- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl) -8- [ (3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] obtained in Reference Example 29 (29b) Phenyl} -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and 3-fluorobenzaldehyde were reacted in the same manner as in the method described in Example 50 (50a) to obtain the title of a white amorphous substance. Compound (95% yield).

(58b) (4S, 9S) -4- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl) -8- [ (3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -4- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] obtained in Example 58 (58a) was used Phenyl} -8- (3-fluorobenzyl) -2,3,4,5,7,8,9,10-octahydro [2,3-g] isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound as a white solid (yield: 98%).

(58c) N-{[(4S, 9S) -4- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl) -8-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -4- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] obtained in Example 58 (58b) was used Phenyl} -8-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-formic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methylsulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a white amorphous substance (yield 61%).

(58d) N-{(4S, 9S) -4- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methoxy] phenyl)- 8-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-{(4S, 9S) -4- {4-[(R)-(3,4-dichlorophenyl) (tetrahydropyran-4-yl) methyl obtained in Example 58 (58c) Oxy] phenyl} -8- (3-fluorobenzyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was performed in the same manner to obtain the title compound as a white solid (yield: 96%).

    Example 59    

N-{(4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8-[(3-fluorophenyl) methyl Radical) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(59a) (4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8-[(3-fluorophenyl) formaldehyde Radical) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

Using (4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 30 (30b), 4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and 3-fluorobenzaldehyde were reacted in the same manner as in the method described in Example 50 (50a) to obtain the title of a white amorphous substance. Compound (yield 50%).

(59b) (4S, 9S) -4- (4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl) -8-[(3-fluorophenyl) formaldehyde Radical) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl) -8-[( 3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound (quantitative) as a white amorphous substance.

(59c) N-{(4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8-[(3-fluorobenzene (Methyl) methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8-[( 3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound (yield 92%) as a white amorphous substance.

(59d) N-{(4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -8-[(3-fluorobenzene (Methyl) methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-{(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8 obtained in Example 59 (59c) -[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was performed in the same manner to obtain the title compound (yield 88%) as a white amorphous substance.

    Example 60    

N-[(4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(60a) (4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28b), 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (218mg, 0.403mmol) and cyclopentanecarboxaldehyde (79μL, 0.807mmol) in dichloromethane (2.69mL) solution, acetic acid was added sequentially (23 μL, 0.403 mmol), sodium triacetoxyborohydride (256 mg, 1.21 mmol), and stirred at room temperature for 1 hour. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 → 85/15) to obtain 201 mg of the title compound as a white amorphous substance (yield: 80). %).

(60b) (4S, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2 , 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy]] obtained in Example 60 (60a) Phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (201 mg, 0.323 mmol) in a solution of tetrahydrofuran (3.23 mL) / methanol (1.61 mL), and under ice-cooling, a 2N-sodium hydroxide aqueous solution ( 1.61 mL, 3.23 mmol) and stirred at room temperature for 16 hours. 2N-hydrochloric acid (1.61 mL, 3.23 mmol) was added to the reaction solution, and the mixture was extracted with dichloromethane (× 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale white amorphous substance. 200 mg of the title compound (quantitative).

(60c) N-[(4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl}- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-dichlorobenzene) obtained in Example 60 (60b) under a nitrogen atmosphere Propyl) propoxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid (197 mg, 0.323 mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenyl obtained in Reference Example 31 To a solution of methyl alanine methanesulfonate (147 mg, 0.388 mmol) in N, N-dimethylformamidine (3.23 mL), under ice cooling, add O- (azabenzitriazole-1) in order. -Yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (160 mg, 0.420 mmol), N, N-diisopropylethylamine (169 μL, 0.969 mmol), under ice cooling , Stirring for 1 hour, followed by 16 hours at room temperature. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with water and saturated brine in this order, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 → 30/70) to obtain 235 mg of the title compound as a white amorphous substance (yield: 83). %).

(60d) N-[(4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

N-[(4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propane) obtained in Example 60 (60c) Oxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (235mg, 0.269mmol) In a solution of tetrahydrofuran (2.69 mL) / methanol (1.34 mL), 2N-sodium hydroxide aqueous solution (1.34 mL, 2.69 mmol) was added under ice-cooling, and the solution was stirred for 0.5 hours under ice-cooling, followed by 1 hour at room temperature. 2N-hydrochloric acid (1.34mL, 2.69mmol) was added to the reaction solution, and the mixture was extracted with dichloromethane / methanol = 9/1 (× 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 209 mg of the title compound (yield 90%) as a white amorphous substance.

    Example 61    

N-[(4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(61a) (4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 30 (30b), 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (207mg, 0.408mmol) and cyclopentanecarboxaldehyde (80μL, 0.816mmol) in dichloromethane (2.72mL), and acetic acid was added sequentially (23 μL, 0.408 mmol), sodium triacetoxyborohydride (259 mg, 1.22 mmol), and stirred at room temperature for 1 hour. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 → 85/15) to obtain 205 mg of the title compound as a white amorphous substance (yield: 85). %).

(61b) (4S, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2 , 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy]] obtained in Example 61 (61a) Phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (205mg, 0.348mmol) in a solution of tetrahydrofuran (3.48mL) / methanol (1.74mL), add 2N-sodium hydroxide aqueous solution under ice cooling (1.74 mL, 3.48 mmol) and stirred at room temperature for 16 hours. 2N-hydrochloric acid (1.74mL, 3.48mmol) was added to the reaction solution, and extracted with dichloromethane (× 2), and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale white amorphous substance 200 mg of the title compound (quantitative).

(61c) N-[(4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl}- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

((4S, 9S) -8- (cyclopentylmethyl) -4- {4-[(1R) -1- (3,4-difluoro) obtained in Example 61 (61b) under a nitrogen atmosphere Phenyl) propoxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid (200 mg, 0.348 mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenyl obtained in Reference Example 31 To a solution of methyl alanine methanesulfonate (159 mg, 0.418 mmol) in N, N-dimethylformamidine (3.48 mL), under ice cooling, add O- (azabenzimidazole-1) in order. -Yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (172 mg, 0.452 mmol), N, N-diisopropylethylamine (182 μL, 1.04 mmol), and ice-cooled Then, it was stirred for 1 hour, followed by 16 hours at room temperature. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 → 30/70) to obtain 222 mg of the title compound as a white amorphous substance (yield 76). %).

(61d) N-[(4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl}- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

N-[(4S, 9S) -8-cyclopentylmethyl-4- {4-[(1R) -1- (3,4-difluorophenyl) propane) obtained in Example 61 (61c) Oxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (222mg, 0.264mmol) In a solution of tetrahydrofuran (2.64 mL) / methanol (1.32 mL), 2N-sodium hydroxide aqueous solution (1.32 mL, 2.64 mmol) was added under ice-cooling, and the solution was stirred for 0.5 hour under ice-cooling, followed by stirring at room temperature for 1 hour. 2N-hydrochloric acid (1.32mL, 2.64mmol) was added to the reaction solution, and the mixture was extracted with dichloromethane / methanol = 9/1 (× 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 218 mg of the title compound as a white amorphous substance (yield 94%).

    Example 62    

N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(62a) (4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28b), 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (210mg, 0.389mmol) and cyclobutanecarboxaldehyde (65μL, 0.778mmol) in dichloromethane (2.59mL) solution, acetic acid was added sequentially (22 μL, 0.389 mmol), sodium triacetoxyborohydride (247 mg, 1.17 mmol), and stirred at room temperature for 1 hour. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 → 80/20) to obtain 215 mg of the title compound as a white amorphous substance (yield 91). %).

(62b) (4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] obtained in Example 62 (62a) Phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (215mg, 0.353mmol) in a solution of tetrahydrofuran (3.53mL) / methanol (1.77mL), add 2N-sodium hydroxide aqueous solution under ice cooling (1.77 mL, 3.53 mmol) and stirred at room temperature for 16 hours. 2N-hydrochloric acid (1.77 mL, 3.53 mmol) was added to the reaction solution, and the mixture was extracted with dichloromethane (× 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale white amorphous substance. 251 mg of the title compound (quantitative).

(62c) N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) obtained in Example 62 (62b) under a nitrogen atmosphere Propoxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid (210 mg, 0.353 mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenyl obtained in Reference Example 31 To a solution of methyl alanine methanesulfonate (161 mg, 0.424 mmol) in N, N-dimethylformamidine (3.53 mL), and under ice-cooling, add O- (azabenzitriazole-1) in order. -Yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (174 mg, 0.459 mmol), N, N-diisopropylethylamine (184 μL, 1.06 mmol), under ice cooling , Stirring for 1 hour, followed by 16 hours at room temperature. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with water and saturated brine in this order, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 → 30/70) to obtain 217 mg of the title compound as a white amorphous substance (yield 71). %).

(62d) N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propane) obtained in Example 62 (62c) Oxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (217mg, 0.252mmol) In a solution of tetrahydrofuran (2.52 mL) / methanol (1.26 mL), a 2N-sodium hydroxide aqueous solution (1.26 mL, 2.52 mmol) was added under ice cooling, and the solution was stirred for 0.5 hours under ice cooling, followed by 1 hour at room temperature. 2N-hydrochloric acid (1.26mL, 2.52mmol) was added to the reaction solution, and the mixture was extracted with dichloromethane / methanol = 9/1 (× 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 207 mg of the title compound as a white amorphous substance (yield 97%).

    Example 63    

N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl} -L-phenylalanine

(63a) (4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

Using (4S, 9S) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 30 (30b), 4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and cyclobutanecarboxaldehyde were reacted in the same manner as in the method described in Example 50 (50a) to obtain the title compound as a white amorphous substance. (84% yield).

(63b) (4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl} -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] obtained in Example 63 (63a) was used Phenyl} -2,3,4,5,7,8,9,10-octahydro [2,3-g] isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound (quantitative) as a pale white amorphous substance.

(63c) N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl}- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] obtained in Example 63 (63b) was used Phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a white amorphous substance (yield 67%).

(63d) N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propoxy] phenyl}- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-difluorophenyl) propane obtained in Example 63 (63c) Oxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 (50d The method described in) was conducted in the same manner to obtain the title compound (yield 96%) as a white amorphous substance.

    Example 64    

N-[(4S, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(64a) (4S, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28b), 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (202 mg, 0.374 mmol) and cyclopentanone (66 μL, 0.747 mmol) in dichloromethane (2.49 mL), and acetic acid ( 21 μL, 0.374 mmol), sodium triacetoxyborohydride (238 mg, 1.12 mmol), and stirred at room temperature for 1 hour. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 → 80/20) to obtain 200 mg of the title compound as a white amorphous substance (yield 88). %).

(64b) (4S, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 64 (64a) } -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (200mg, 0.329mmol) in a solution of tetrahydrofuran (3.29mL) / methanol (1.64mL), add 2N-sodium hydroxide aqueous solution under ice cooling (1.64 mL, 3.29 mmol) and stirred at room temperature for 16 hours. 2N-hydrochloric acid (1.64mL, 3.29mmol) was added to the reaction solution, and the solution was extracted with dichloromethane (× 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale white amorphous substance. 195 mg of the title compound (quantitative).

(64c) N-[(4S, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2, 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 64 (64b) under a nitrogen atmosphere Phenyl] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid (195 mg, 0.329 mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenyl obtained in Reference Example 31 To a solution of methyl alanine methanesulfonate (150 mg, 0.395 mmol) in N, N-dimethylformamidine (3.29 mL), under ice cooling, add O- (azabenzitriazole-1) in order. -Yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (163 mg, 0.428 mmol), N, N-diisopropylethylamine (172 μL, 0.987 mmol), under ice cooling , Stirring for 1 hour, followed by 16 hours at room temperature. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with water and saturated brine in this order, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 → 30/70) to obtain 208 mg of the title compound (yield: 73) as a white amorphous substance. %).

(64d) N-[(4S, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2, 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

N-[(4S, 9S) -8-cyclopentyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 64 (64c) ] Phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (208 mg, 0.242 mmol) In a solution of tetrahydrofuran (2.42 mL) / methanol (1.21 mL), a 2N-sodium hydroxide aqueous solution (1.21 mL, 2.42 mmol) was added under ice-cooling, and the solution was stirred for 0.5 hours under ice-cooling, followed by 1 hour at room temperature. 2N-hydrochloric acid (1.21mL, 2.42mmol) was added to the reaction solution, and the mixture was extracted with dichloromethane / methanol = 9/1 (× 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 190 mg of the title compound as a pale white amorphous substance (yield 93%).

    Example 65    

N-[(4S, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(65a) (4S, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

Using (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28b), 4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and cyclobutanone were reacted in the same manner as in the method described in Example 50 (50a) to obtain the title compound (amorphous white substance) Yield 88%).

(65b) (4S, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 65 (65a) was used } -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound (quantitative) as a pale white amorphous substance.

(65c) N-[(4S, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2, 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 65 (65b) was used } -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound (yield 56%) as a white amorphous substance.

(65d) N-[(4S, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2, 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-[(4S, 9S) -8-cyclobutyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 65 (65c) ] Phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 (50d The method described in) was performed in the same manner to obtain the title compound (yield 90%) as a pale white amorphous substance.

    Example 66    

N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (2-methylpropyl)- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(66a) (4S, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8- (2-methylpropyl)- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

Using (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28b), 4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and 2-methylpropanal were reacted in the same manner as in the method described in Example 50 (50a) to obtain a white amorphous substance. Title compound (quantitative).

(66b) (4S, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8- (2-methylpropyl)- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (2 obtained in Example 66 (66a) -Methylpropyl) -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound (quantitative) as a pale white amorphous substance.

(66c) N-[(4S, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8- (2-methylpropane Radical) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (2 obtained in Example 66 (66b) -Methylpropyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound (yield 75%) as a white amorphous substance.

(66d) N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (2-methylpropane Radical) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8 obtained in Example 66 (66c) -(2-methylpropyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound (quantitative) as a pale white amorphous substance.

    Example 67    

N-[(4S, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2 , 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(67a) (4S, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2 , 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

Using (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28b), 4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and cyclopropanecarboxaldehyde were reacted in the same manner as in the method described in Example 50 (50a) to obtain the title compound (amorphous white substance) 70% yield).

(67b) (4S, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2 , 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 67 (67a) was used Phenyl] phenyl} -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound (quantitative) as a pale white amorphous substance.

(67c) N-[(4S, 9S) -8- (cyclopropylmethyl) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl } -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -8- (cyclopropylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 67 (67b) was used Phenyl] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a white amorphous substance (yield 67%).

(67d) N-[(4S, 9S) -8- (cyclopropylmethyl) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl } -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-[(4S, 9S) -8- (cyclopropylmethyl) -4- {4-[(11) -1- (3,4-dichlorophenyl) obtained in Example 67 (67c) ) Propoxy] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound as a pale white amorphous substance (yield: 94%).

    Example 68    

N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-propyl-2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(68a) (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-propyl-2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

Using (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28b), 4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-formic acid methyl ester and propionaldehyde were reacted in the same manner as in the method described in Example 50 (50a) to obtain the title compound as a white amorphous substance (product (76%).

(68b) (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-propyl-2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-propyl obtained in Example 68 (68a) was used -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound (quantitative) as a pale white amorphous substance.

(68c) N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-propyl-2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-propyl obtained in Example 68 (68b) was used -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a white amorphous substance (yield: 63%).

(68d) N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8-propyl-2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8 obtained in Example 68 (68c) -Propyl-2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 (50d The method described in) was conducted in the same manner to obtain the title compound (yield 86%) as a pale white amorphous substance.

    Example 69    

N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (propane-2-yl) -2 , 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(69a) (4S, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8- (propane-2-yl) -2 , 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

Using (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28b), 4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and acetone were reacted in the same manner as in the method described in Example 50 (50a) to obtain the title compound as a white amorphous substance (yield). 80%).

(69b) (4S, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8- (propane-2-yl) -2 , 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (propane obtained from Example 69 (69a) was used -2-yl) -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound (quantitative) as a pale white amorphous substance.

(69c) N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (propane-2-yl ) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (propane obtained from Example 69 (69b) was used -2-yl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound (yield 71%) as a white amorphous substance.

(69d) N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (propane-2-yl ) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Use N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (Propane-2-yl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound as a pale white amorphous substance (yield: 99%).

    Example 70    

N-[(4S, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(70a) (4S, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28b), 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (220mg, 0.407mmol) and [(1-ethoxycyclopropyl) oxy] (trimethyl) silane (511 μL, 2.44mmol ) In a methanol (2.04 mL) solution, acetic acid (233 μL, 4.07 mmol), sodium cyanoborohydride (135 mg, 2.04 mmol) were sequentially added, and the mixture was stirred at 60 ° C. for 6 hours. After the reaction solution was allowed to cool to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate (× 2), washed with saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 → 75/25) to obtain 215 mg of the title compound as a white amorphous substance (yield 90). %).

(70b) (4S, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl obtained in Example 70 (70a) } -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (212mg, 0.365mmol) in a solution of tetrahydrofuran (3.65mL) / methanol (1.83mL), add 2N-sodium hydroxide aqueous solution under ice cooling (1.83 mL, 3.65 mmol) and stirred at room temperature for 16 hours. 2N-hydrochloric acid (1.83mL, 3.65mmol) was added to the reaction solution, and extracted with dichloromethane (× 2), and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale white amorphous substance 207 mg of the title compound (quantitative).

(70c) N-[(4S, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2, 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 70 (70b) under a nitrogen atmosphere Phenyl] phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid (207 mg, 0.365 mmol) and 4- (2,3-dimethylpyridin-4-yl) -L-phenyl obtained in Reference Example 31 To a solution of methyl alanine methane sulfonate (167 mg, 0.438 mmol) in N, N-dimethylformamidine (3.65 mL), and under ice cooling, O- (azabenzimidazol-1) was sequentially added. -Yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (180 mg, 0.475 mmol), N, N-diisopropylethylamine (191 μL, 1.10 mmol), under ice cooling , Stirring for 1 hour, followed by 16 hours at room temperature. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with water and saturated brine in this order, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 → 30/70) to obtain 241 mg of the title compound as a white amorphous substance (yield 79). %).

(70d) N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl}- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

N-[(4S, 9S) -8-cyclopropyl-4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy) obtained in Example 70 (70c) ] Phenyl} -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester (241 mg, 0.289 mmol) In a solution of tetrahydrofuran (2.89 mL) / methanol (1.45 mL), 2N-sodium hydroxide aqueous solution (1.45 mL, 2.89 mmol) was added under ice-cooling, and the solution was stirred for 0.5 hours under ice-cooling, followed by 1 hour at room temperature. 2N-hydrochloric acid (1.45mL, 2.89mmol) was added to the reaction solution, and the mixture was extracted with dichloromethane / methanol = 9/1 (× 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 229 mg of the title compound as a pale white amorphous substance (yield 97%).

    Example 71    

N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7 , 8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(71a) (4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7 , 8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7, obtained in Reference Example 20 (20b), 8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and cyclobutanecarboxaldehyde were reacted in the same manner as in the method described in Example 50 (50a) to obtain the title compound as a white amorphous substance. (94% yield).

(71b) (4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7 , 8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2 obtained in Example 71 (71a), 3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as described in Example 50 (50b) to obtain the title compound (quantitative) as a white solid.

(71c) N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2 obtained in Example 71 (71b), 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a white amorphous substance (yield: 73%).

(71d) N-[(4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-{[((4S, 9S) -8- (cyclobutylmethyl) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl) obtained in Example 71 (71c) } -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound as a white solid (yield 90%).

    Example 72    

N-[(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2-methylpropyl) -2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(72a) (4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2-methylpropyl) -2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7, obtained in Reference Example 20 (20b), 8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and 2-methylpropanal were reacted in the same manner as in the method described in Example 50 (50a) to obtain a white amorphous substance. The title compound (96% yield).

(72b) (4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2-methylpropyl) -2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -4- {4-[(3,4-dichlorobenzyl) oxy] phenyl} -8- (2-methylpropyl)-obtained in Example 72 (72a) was used 2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound as a white solid (yield 97%).

(72c) N-{[(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2-methylpropyl) -2, 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2-methylpropyl) obtained in Example 72 (72b) was used -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound (yield 96%) as a white amorphous substance.

(72d) N-[(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2-methylpropyl) -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-[(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2-methyl obtained in Example 72 (72c) (Propyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound (quantitative) as a pale white amorphous substance.

    Example 73    

N-[(4S, 9S) -8-cyclobutyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7,8 , 9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(73a) (4S, 9S) -8-cyclobutyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7,8 , 9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7, obtained in Reference Example 20 (20b), 8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and cyclobutanone were reacted in the same manner as described in Example 50 (50a) to obtain the title compound as a white solid (yield 94%) ).

(73b) (4S, 9S) -8-cyclobutyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7,8 , 9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

Using (4S, 9S) -8-cyclobutyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3, obtained in Example 73 (73a), 4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound as a white solid (yield: 92%).

(73c) N-[(4S, 9S) -8-cyclobutyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5, 7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

Using (4S, 9S) -8-cyclobutyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3, obtained in Example 73 (73b), 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a white amorphous substance (yield: 73%).

(73d) N-[(4S, 9S) -8-cyclobutyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5, 7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-[(4S, 9S) -8-cyclobutyl-4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2 obtained in Example 73 (73c) , 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound (quantitative) as a pale white amorphous substance.

    Example 74    

N-{(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(1S) -1-phenylpropyl] -2, 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine or N-{(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(1R) -1-phenylpropyl] -2,3,4,5,7, 8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine (optically active substance 1)

(74a) (4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (1-phenylpropyl) -2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9carboxylic acid methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4, obtained in Reference Example 20 (20b) under a nitrogen atmosphere, 5,7,8,9,10-octahydro [2,3-g] isoquinoline-9-carboxylic acid methyl ester (511 mg, 0.997 mmol) in N, N-dimethylformamide (9.97 mL) solution, and Synthetic Communications, 2005, 35, (1-Bromopropyl) benzene (993 mg, 4.99 mmol) and sodium bicarbonate (419 mg, 4.99 mmol) described in 2795-2800, and stirred at room temperature for 7 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 → 80/20) to obtain 398 mg of the title compound as a colorless oily substance (yield 63%). .

(74b) (4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (1-phenylpropyl) -2,3,4, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (1-phenylpropyl) obtained in Example 74 (74a) was used -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound as a white amorphous substance (yield 97%). ).

(74c) N-{(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (1-phenylpropyl) -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (1-phenylpropyl) obtained in Example 74 (74b) was used -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound (yield: 58%) as a white amorphous substance.

(74d) N-{(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(1S) -1-phenylpropyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester or N-({(4S , 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(1R) -1-phenylpropyl] -2,3,4,5 , 7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

The N-{(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (1-phenyl) obtained in Example 74 (74c) (Propyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester by high speed liquid chromatography ( Column: DAICEL CHIRALPAK IC; mobile phase: n-hexane / ethanol), and a white amorphous material was obtained as isomer 1 of the first peak (yield 40%, retention time: 14.36min). In addition, a white amorphous substance was obtained as the second isomer 2 (yield 38%, retention time: 16.64 min).

(74e) N-{(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(1S) -1-phenylpropyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine or N-({(4S, 9S ) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(1R) -1-phenylpropyl] -2,3,4,5,7 , 8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using the isomer 1 obtained in Example 74 (74d), the same reaction was performed as in the method described in Example 50 (50d) to obtain the title compound (quantitative) as a pale yellow amorphous substance.

    Example 75    

N-{(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(1S) -1-phenylpropyl] -2, 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine or N-({(4S, 9S ) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(1R) -1-phenylpropyl] -2,3,4,5,7 , 8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

The isomer 2 obtained in Example 74 (74d) was used. The reaction was carried out in the same manner as the method described in Example 50 (50d) to obtain the title compound as a pale yellow amorphous substance (yield: 83%).

    Example 76    

N-{(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(pyridin-2-yl) methyl] -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(76a) (4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(pyridin-2-yl) methyl] -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7, obtained in Reference Example 20 (20b), 8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (50mg, 0.091mmol) in N, N-dimethylformamide (2mL) solution, 2- (bromomethyl) pyridine bromide was added Hydrogen chloride (58 mg, 0.23 mmol) and sodium bicarbonate (38 mg, 0.46 mmol) were stirred at room temperature for 8.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 96/4 → 50/50 → 30: 70) to obtain 40 mg of the title compound (produced as a colorless oily substance) Rate 72%).

(76b) (4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(pyridin-2-yl) methyl] -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(pyridin-2-yl) obtained in Example 76 (76a) was used (Methyl) -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as described in Example 50 (50b) to obtain the title compound as a pale yellow amorphous substance (yield 93% ).

(76c) N-{(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(pyridin-2-yl) methyl]- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(pyridin-2-yl) obtained in Example 76 (76b) was used (Methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound (yield 62%) as a light brown amorphous substance.

(76d) N-{(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(pyridin-2-yl) methyl]- 2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-{(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(pyridine-2) obtained in Example 76 (76c) -Yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound (yield 84%) as a yellow amorphous substance.

    Example 77    

N-{(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(2-fluorophenyl) methyl] -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(77a) (9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(2-fluorophenyl) methyl] -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4,5,7,8, obtained in Reference Example 21 (21b), 9,10-octahydro To a solution of [2,3-g] isoquinoline-9-carboxylic acid methyl ester (56 mg, 0.109 mmol) in N, N-dimethylformamide (1 mL), 1- (bromomethyl)- 2-Fluorobenzene (16 μL, 0.131 mmol) and potassium carbonate (45 mg, 0.328 mmol) were stirred at room temperature for 1.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 → 70/30) to obtain 39 mg of the title compound as a white amorphous substance (yield: 57). %).

(77b) (9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(2-fluorophenyl) methyl] -2,3,4 , 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(2-fluorophenyl) methyl obtained in Example 77 (77a) was used ] -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound as a white solid (yield: 99%).

(77c) N-{(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(2-fluorophenyl) methyl] -2, 3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(2-fluorophenyl) methyl obtained in Example 77 (77b) ] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a colorless oily substance (yield 67%).

(77d) N-{(9S) -4- {4-[(3,4-dichlorobenzyl) oxy] phenyl} -8-[(2-fluorophenyl) methyl] -2,3 , 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-{(9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(2-fluorophenyl) obtained in Example 77 (77c) ) Methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound as a colorless amorphous substance (yield: 53%).

    Example 78    

N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) -2-hydroxyethoxy] phenyl} -8-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(78a) (9S) -4- {4- [2- (Ethyloxy) -1- (3,4-dichlorophenyl) ethoxy] phenyl} -8-[(3-fluorobenzene (Methyl) methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4- [2- (Ethyloxy) -1- (3,4-dichlorophenyl) ethoxy] phenyl} -2 obtained in Reference Example 26 (26f) , 3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and 3-fluorobenzyl bromide were reacted in the same manner as in the method described in Example 76 (76a) to obtain the title compound as a colorless solid (product Rate 93%).

(78b) (9S) -4- {4- [1- (3,4-dichlorophenyl) -2-hydroxyethoxy] phenyl} -8-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(9S) -4- {4- [2- (Ethyloxy) -1- (3,4-dichlorophenyl) ethoxy] phenyl} -8 obtained in Example 78 (78a) was used -[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound as a colorless solid (yield: 99%).

(78c) N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) -2-hydroxyethoxy] phenyl} -8-[(3-fluorophenyl) (Methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(9S) -4- {4- [1- [3,4-dichlorophenyl) -2-hydroxyethoxy] phenyl} -8-[(3- (Fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as described in Example 50 (50c) to obtain the title compound as a colorless solid (yield 76%).

(78d) N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) -2-hydroxyethoxy] phenyl} -8-[(3-fluorophenyl) (Methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) -2-hydroxyethoxy] phenyl} -8- [obtained in Example 78 (78c) (3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinolin-9-yl] carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 The method described in (50d) was conducted in the same manner to obtain the title compound as a colorless solid (yield: 77%).

    Example 79    

N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (2,2,2-trifluoro (Ethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(79a) (4S, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8- (2,2,2-trifluoro (Ethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

Using (4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -2,3, obtained in Reference Example 28 (28b), 4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and 2,2,2-trifluoroethyltrifluoromethanesulfonate were reacted in the same manner as in the method described in Example 76 (76a). The title compound was obtained as a pale yellow amorphous substance (yield 60%).

(79b) (4S, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8- (2,2,2-trifluoro (Ethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8- (2 obtained in Example 79 (79a) , 2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound (quantitative) as a white amorphous substance.

(79c) N-[(4S, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8- (2,2,2 -Trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8- (2 obtained in Example 79 (79b) , 2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a white amorphous substance (yield: 83%).

(79d) N-[(4S, 9S) -4- (4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl) -8- (2,2,2 -Trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-[(4S, 9S) -4- {4-[(1R) -1- (3,4-dichlorophenyl) propoxy] phenyl} -8 obtained in Example 79 (79c) -(2,2,2-trifluoroethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound (yield 86%) as a white amorphous substance.

    Example 80    

N-[(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2,5-dimethyl-1,3- Azole-4-carbonyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(80a) (4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2,5-dimethyl-1,3- Azole-4-carbonyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -2,3,4, obtained in Reference Example 20 (20b) under a nitrogen atmosphere, 5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester (50mg, 0.091mmol) in N, N-dimethylformamide (2mL) solution, 2,5-dimethyl chloride was added Base-1,3- Azole-4-carboxylic acid (19 mg, 0.14 mmol), 4- (4,6-dimethoxy-1,3,5-tri -2-yl) -4-methyl Porphyrinium hydrate (50 mg, 0.18 mmol) and triethylamine (51 μL, 0.36 mmol) were stirred at room temperature for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (× 2), washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 30/70 → 0: 100) to obtain 58 mg of the title compound (quantitative) as a white amorphous substance. .

(80b) (4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2,5-dimethyl-1,3- Azole-4-carbonyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8-[(2,5-dimethyl) obtained in Example 80 (80a) was used Base-1,3- Azole-4-yl) carbonyl] -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as described in Example 50 (50b) to obtain the title compound as a white amorphous substance (yield 96%). ).

(80c) N-{[(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2,5-dimethyl-1, 3- Azole-4-carbonyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2,5-dimethyl) obtained in Example 80 (80b) -1,3- Azole-4-carbonyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid salt was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a light brown amorphous substance (yield: 39%).

(80d) N-[(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2,5-dimethyl-1,3 - Azole-4-carbonyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using N-[(4S, 9S) -4- {4-[(3,4-dichlorophenyl) methoxy] phenyl} -8- (2,5- Dimethyl-1,3- Azole-4-carbonyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl] -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, and Example 50 (50d The method described in) was performed in the same manner to obtain the title compound (quantitative) as a yellow amorphous substance.

    Example 81    

2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8- [2- (dimethylamino)- 2-oxoethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

(81a) (9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8- [2- (dimethylamino) -2- pendant oxygen (Ethylethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- {4- [1- [3,4-dichlorophenyl) propoxy] phenyl} -2,3,4,5,7, obtained in Reference Example 25 (25b), 8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and 2-bromo-N, N-dimethylacetamidinide were reacted in the same manner as described in Example 76 (76a) to obtain The title compound as a colorless solid (86% yield).

(81b) (9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8- [2- (dimethylamino) -2- pendant oxygen (Ethylethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(9S) -4- {4- [1- [3,4-dichlorophenyl) propoxy] phenyl} -8- [2- (dimethylamine) obtained in Example 81 (81a) was used (Yl) -2-oxoethyl) -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound (quantitative) as a colorless solid.

(81c) 2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8- [2- (dimethylamine (Yl) -2-oxoethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(9S) -4- {4- [1- [3,4-dichlorophenyl) propoxy] phenyl} -8- [2- (dimethylamine) obtained in Example 81 (81b) was used (Yl) -2-oxoethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 2-chloro-4- (2,3-dimethylpyridin-4-yl) -L-benzene obtained in Reference Example 32 (32d) The methyl alanine dihydrochloride was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a colorless solid (yield: 81%).

(81d) 2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8- [2- (dimethylamine (Yl) -2-oxoethyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using 2-chloro-N-{(9S) -4- {4- [1- (3,4-dichlorophenyl) propoxy] phenyl} -8- [obtained in Example 81 (81c) 2- (dimethylamino) -2-oxoethyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound as a colorless solid (yield 75%).

    Example 82    

2-chloro-N-{(9S) -4- (4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} phenyl} -8-[(pyridine-2 -Yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (82a) 1,3-difluoro-5- [2- (4-nitrophenoxy) propane-2-yl] benzene    

Under a nitrogen atmosphere, in a solution of 2- (3,5-difluorophenyl) propane-2-ol (2.01 g, 11.7 mmol) in N, N-dimethylformamide (39 mL) described in US2014 / 200227 Under ice cooling, sodium hydride (60 wt%, 514 mg, 12.8 mmol) was added, and after stirring for 15 minutes, 4-fluoronitrobenzene (1.35 mL, 12.8 mmol) was added, and the mixture was stirred at room temperature for 6 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 30/1 → 19/1) to obtain 2.17 g of the title compound as a pale yellow oily substance (yield: 63%).

    (82b) 4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} aniline    

Acetic acid (21 mL) of 1,3-difluoro-5- [2- (4-nitrophenoxy) propane-2-yl] benzene (2.17 g, 7.40 mmol) obtained in Example 82 (82a) Zinc powder (2.90 g, 44.4 mmol) was added to the solution, and stirred at room temperature for 20 minutes. Then, after stirring at 40 degreeC for 2 hours, it diluted with ethyl acetate and neutralized with potassium carbonate aqueous solution. The organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 19/1 → 3/1) to obtain 1.13 g of the title compound as a pale yellow oily substance (yield: 58%).

    (82c) 1,3-difluoro-5- [2- (4-iodophenoxy) propane-2-yl] benzene    

4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} aniline (830 mg, 3.15 mmol) in acetonitrile (6.3 mL) obtained in Example 82 (82b) To a solution of methyl iodide (6.3 mL), tertiary butyl nitrite (747 μL, 6.31 mmol) was added at room temperature, and after stirring at 50 ° C. for 1 hour, tertiary butyl nitrite (373 μL, 3.15 mmol) was added and stirred. 2 hours. After the reaction solution was diluted with acetonitrile (6.3 mL), piperidine (25 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. It was diluted with ethyl acetate, washed with a 1N-hydrochloric acid aqueous solution and saturated brine in this order, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 30/1) to obtain 612 mg of the title compound as a yellow oily substance (yield 52%).

    (82d) (3S) -6- (benzyloxy) -7-[(trifluoromethanesulfonyl) oxy] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester    

(3S) -6- (Benzyloxy) -7-[(trifluoromethanesulfonyl) oxy] -3,4-dihydroisoquinoline-2,3 obtained in Reference Example 16 (16f) was used (1H) -Dicarboxylic acid 2-tert-butyl 3-methyl ester was reacted in the same manner as in the method described in Reference Example 23 (23b) to obtain the title compound (quantitative) as a yellow oily substance.

    (82e) (3S) -6- (benzyloxy) -2-[(pyridin-2-yl) methyl] -7-[(trifluoromethanesulfonyl) oxy] -1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid methyl ester    

(3S) -6- (Benzyloxy) -7-[(trifluoromethanesulfonyl) oxy] -1,2,3,4-tetrahydroisoquinoline obtained from Example 82 (82d) was used Methyl-3-carboxylic acid and pyridine-2-carboxaldehyde were reacted in the same manner as described in Example 50 (50a) to obtain the title compound as a colorless oily substance (yield: 83%).

    (82f) (3S) -6- (benzyloxy) -7- (4-hydroxybut-1-yn-1-yl) -2-[(pyridin-2-yl) methyl] -1,2, 3,4-Tetrahydroisoquinoline-3-carboxylic acid methyl ester    

(3S) -6- (Benzyloxy) -2-[(pyridin-2-yl) methyl] -7-[(trifluoromethanesulfonyl) oxy] obtained in Example 82 (82e) was used. -1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid methyl ester was reacted in the same manner as described in Reference Example 16 (16g) to obtain the title compound as a pale yellow amorphous substance (yield 77%).

    (82g) (3S) -6- (benzyloxy) -7-[(1E) -2- (4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} Phenyl) -4-hydroxybut-1-en-1-yl] -2-[(pyridin-2-yl) methyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Ester    

(3S) -6- (Benzyloxy) -7- (4-hydroxybut-1-yn-1-yl) -2-[(pyridin-2-yl) methyl obtained in Example 82 (82f) was used Methyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and 1,3-difluoro-5- [2- (4-iodophenoxy) obtained in Example 82 (82c) Group) propane-2-yl] benzene was reacted in the same manner as described in Reference Example 16 (16h) to obtain the title compound as a colorless solid (yield 7.2%).

    (82h) (3S) -7- [2- (4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} phenyl) -4-hydroxybutyl] -6 -Hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester    

(3S) -6- (benzyloxy) -7-[(1E) -2- (4-{[2- (3,5-difluorophenyl) propane-propane- 2-yl] oxy} phenyl) -4-hydroxybut-1-en-1-yl] -2-[(pyridin-2-yl) methyl] -1,2,3,4-tetrahydroiso The quinoline-3-carboxylic acid methyl ester was reacted in the same manner as in the method described in Reference Example 16 (16i) to obtain the title compound as a colorless solid (yield: 51%).

    (82i) (3S) -7- [2- (4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} phenyl) -4-hydroxybutyl] -6 -Hydroxy-2-[(pyridin-2-yl) methyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester    

(3S) -7- [2- (4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} phenyl) -4 obtained in Example 82 (82h) was used -Hydroxybutyl] -6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester and pyridine-2-carboxaldehyde were reacted in the same manner as in the method described in Example 50 (50a). The title compound was obtained as a colorless solid (yield: 85%).

(82j) (9S) -4- (4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} phenyl) -8-[(pyridin-2-yl) methyl Radical) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(3S) -7- [2- (4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} phenyl) -4 obtained in Example 82 (82i) was used -Hydroxybutyl] -6-hydroxy-2-[(pyridin-2-yl) methyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester, as in Reference Example 16 (16j The method described in) was carried out in the same manner to obtain the title compound (58%) as a colorless solid.

(82k) (9S) -4- (4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} phenyl) -8-[(pyridin-2-yl) methyl Radical) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(9S) -4- (4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} phenyl) -8-[( Pyridin-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro [2,3-g] isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as in the method described in Example 50 (50b) to obtain the title compound as a colorless solid (yield: 88%).

(821) 2-chloro-N-{(9S) -4- (4-{[2- (3,5-difluorophenyl) propane-2-ylmethyl] oxy} phenyl) -8- [(Pyridin-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(9S) -4- (4-{[2- (3,5-difluorophenyl) propane-2-yl] oxy} phenyl) -8-[( Pyridin-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 2-chloro-4- (2,3-dimethylpyridin-4-yl) -L-benzene obtained in Reference Example 32 (32d) The methyl alanine dihydrochloride was reacted in the same manner as the method described in Example 50 (50c) to obtain the title compound (yield: 59%) as a light brown solid.

(82m) 2-chloro-N-{(9S) -4- (4-{[2- (3,5-difluorophenyl) propane-2-ylmethyl] oxy} phenyl) -8- [(Pyridin-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

Using 2-chloro-N-{(9S) -4- (4-{[2- (3,5-difluorophenyl) propane-2-ylmethyl] oxy obtained from Example 82 (82l) } Phenyl) -8-[(pyridin-2-yl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound as a colorless solid (yield 75%).

    Example 83    

N-{(9S) -4- (4-{[3- (3,4-dichlorophenyl) oxyfluoren-3-yl] oxy} phenyl) -8-[(3-fluorophenyl) (Methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

    (83a) 3- (3,4-dichlorophenyl) oxo-3-ol    

Under a nitrogen atmosphere, in a solution of 3-oxetanone (400 mg, 5.6 mmol) in tetrahydrofuran (8 mL), under ice cooling, 3,4-dichlorobenzene bromide was added little by little over 15 minutes. After magnesium (0.5M-tetrahydrofuran solution, 12 mL, 6.1 mmol) was stirred under ice-cooling for 1 hour. After warming to room temperature, a saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. After washing with water and saturated brine in this order, drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 → 50/50) to obtain 466 mg of the title compound as a white solid (yield 38%).

    (83b) 3- (3,4-dichlorophenyl) oxo-3-yl methanesulfonate    

In a solution of 3- (3,4-dichlorophenyl) oxo-3-ol (200 mg, 0.91 mmol) in dichloromethane (2 mL) obtained in Example 83 (83a), under ice cooling, sequentially Triethylamine (0.40 mL) and methanesulfonyl chloride (0,10 mL, 1.3 mmol) were added, and the mixture was stirred for 3 hours under ice-cooling. The reaction solution was diluted with dichloromethane, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 299 mg of the title compound as an orange oily substance (yield: 99%).

(83c) (9S) -4- (4-hydroxyphenyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- (4-hydroxyphenyl) -2,3,4,5,9,10-hexahydro obtained in Reference Example 16 (16j) was used 呯 幷 [2,3-g] isoquinoline-8,9 (7H) -dicarboxylic acid 8-tert-butyl 9-methyl ester was reacted in the same manner as described in Reference Example 20 (20b) to obtain The title compound was obtained as a white solid (78% yield).

(83d) (9S) -8-[(3-fluorophenyl) methyl] -4- (4-hydroxyphenyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -4- (4-hydroxyphenyl) -2,3,4,5,7,8,9,10-octahydro obtained in Example 83 (83c) [2,3-g] Isoquinoline-9-carboxylic acid methyl ester and 1- (bromomethyl) -3-fluorobenzene were reacted in the same manner as in the method described in Example 77 (77a), and the reaction was light. The title compound is a yellow amorphous material (70% yield).

(83e) (9S) -4- (4-{[3- (3,4-dichlorophenyl) oxo-3-yl] oxy} phenyl) -8-[(3-fluorophenyl) (Methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid methyl ester

(9S) -8-[(3-fluorophenyl) methyl] -4- (4-hydroxyphenyl) -2,3,4,5, obtained in Example 83 (83d) under a nitrogen atmosphere, 7,8,9,10-octahydro To a solution of [2,3-g] isoquinoline-9-carboxylic acid methyl ester (30 mg, 0.065 mmol) in N, N-dimethylformamide (0.5 mL), add The obtained 3- (3,4-dichlorophenyl) oxo-3-ylmethanesulfonate (40 mg, 0.130 mmol) and cesium carbonate (65 mg, 0.196 mmol) were stirred at 80 ° C for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 → 70/30) to obtain 15 mg of the title compound (yield: 35) as a pale yellow amorphous substance. %).

(83f) (9S) -4- (4-{[3- (3,4-dichlorophenyl) oxyfluoren-3-yl] oxy} phenyl} -8-[(3-fluorophenyl) (Methyl) -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid

(9S) -4- (4-{[3- (3,4-dichlorophenyl) oxyfluoren-3-yl] oxy} phenyl} -8- [obtained in Example 83 (83e) was used (3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro [2,3-g] Isoquinoline-9-carboxylic acid methyl ester was reacted in the same manner as described in Example 50 (50b) to obtain the title compound (quantitative) as a white solid.

(83g) N-{(9S) -4- (4-{[3- (3,4-dichlorophenyl) oxyfluoren-3-yl] oxy} phenyl) -8-[(3-fluoro (Phenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester

(9S) -4- (4-{[3- (3,4-dichlorophenyl) oxo-3-yl] oxy} phenyl} -8- [obtained in Example 83 (83f) was used (3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carboxylic acid and 4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl methanesulfonate obtained in Reference Example 31 The acid was reacted in the same manner as in the method described in Example 50 (50c) to obtain the title compound as a white amorphous substance (yield 68%).

(83h) N-{(9S) -4- (4-{[3- (3,4-dichlorophenyl) oxyfluoren-3-yl] oxy} phenyl) -8-[(3-fluoro (Phenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine

N-{(9S) -4- (4-{[3- (3,4-dichlorophenyl) oxyfluoren-3-yl] oxy} phenyl)-obtained in Example 83 (83g) was used 8-[(3-fluorophenyl) methyl] -2,3,4,5,7,8,9,10-octahydro 呯 幷 [2,3-g] isoquinoline-9-carbonyl} -4- (2,3-dimethylpyridin-4-yl) -L-phenylalanine methyl ester, as in Example 50 (50d The method described in) was carried out in the same manner to obtain the title compound as a white solid (yield: 73%).

Hereinafter, the structural formulas of the compounds described in Reference Examples and Examples and their physicochemical data are summarized as follows.

Claims (25)

A compound represented by the general formula (I) or a pharmacologically acceptable salt thereof, [Wherein each substituent is defined as follows: R ¹ : C3-C6 cycloalkyl, phenyl which may be substituted with 1 or 2 halogen atoms, or 6-membered heterocyclic ring which may be substituted with 1 or 2 halogen atoms Aryl (However, in the case where R ¹ is a phenyl group which may be substituted with 1 or 2 halogen atoms, the phenyl group may form an ortho position and combine with the terminal of the C1-C6 alkyl group of R ² to form a ring and include R ¹ and R ² is a carbon atom indenane ring or tetralin ring), R ² : hydrogen atom, C1-C6 alkyl group, C3-C6 cycloalkyl group, hydroxyl C1-C6 alkyl group, C1-C6 alkoxy group A C1-C6 alkyl group, or a C3-C5 saturated cyclic ether group, R ³ : a hydrogen atom, or a C1-C6 alkyl group (however, R ² and R ³ may form a terminal bond and include their direct bond C3-C5 saturated cyclic ether of carbon atom), R ⁴ : hydrogen atom, or halogen atom, R ⁵ : C1-C6 alkyl, halogen C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 (Cycloalkyl) methyl, methyl substituted with C3-C5 saturated cyclic ether, bis (C1-C6 alkyl) aminomethylmethyl, 5 substituted by 1 or 2 C1-C6 alkyl 5-membered ring heteroaryl carbonyl, 5- or 6-membered ring heteroaryl C1-C6 alkyl which may be substituted by 1 or 2 C1-C6 alkyl groups, or 1- or 2-membered C1-C6 alkyl groups Or a phenyl C1-C6 alkyl group which may be substituted with 1 or 2 halogen atoms, R ⁶ : a hydrogen atom, or a halogen atom, R ⁷ : a 6-membered heterocyclic ring which may be substituted with 1 or 2 C1-C6 alkyl groups Aryl, X: -CH ₂ -,-(C1-C6 alkyl) N-,-((C1-C6 alkyl) carbonyl) N-, or -O-, Y: -CH ₂ -,-(C1 -C6 alkyl) N-,-((C1-C6 alkyl) carbonyl) N-, or -O-, Z: -CH _2- , or -O- (except when X contains N or O, Y Is -CH _2- , and when Y contains N or O, X is -CH _2- )]. For example, the compound of claim 1 or a pharmacologically acceptable salt thereof, wherein R ¹ is a phenyl group substituted with 1 or 2 halogen atoms, and R ⁴ and R ⁶ are hydrogen atoms. The compound of claim 1 or 2 or a pharmacologically acceptable salt thereof, wherein R ⁷ is pyridyl substituted with 1 or 2 C1-C6 alkyl groups. The compound of any one of claims 1 to 3 or a pharmacologically acceptable salt thereof, wherein R ⁵ is C1-C6 alkyl, halo C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 ring Alkyl) methyl, 6-membered ring heteroaryl C1-C6 alkyl, which may be substituted with 1 or 2 C1-C6 alkyl groups, or C1-C6 alkyl, which may be substituted with 1 or 2 groups, or 1 or 2 2 halogen atoms substituted phenyl C1-C6 alkyl. The compound of claim 1, or a pharmacologically acceptable salt thereof, wherein each substituent is selected from the group of substituents: R ¹ : 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3, 4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, or 4-chloro-3-fluorophenyl, R ² : hydrogen atom, methyl, ethyl, propyl Group, cyclopropyl, cyclopentyl, cyclohexyl, oxyfluorenyl, tetrahydropiperanyl, or hydroxymethyl, R ³ : a hydrogen atom, or a methyl group (however, R ² and R ³ may form a terminal bond Oxo rings which are bound and contain carbon atoms which are directly bonded to them), R ⁴ : hydrogen atom or fluorine atom, R ⁵ : methyl, ethyl, propyl, isopropyl, isobutyl, 2,2 , 2-trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, 1-phenylpropyl, or 2-pyridylmethyl, R ⁶ : hydrogen atom or chlorine atom, R ⁷ : 2,3-dimethyl-4-pyridyl, X: -CH ₂ -,-(CH ₃ ) N-,-( CH ₃ CH ₂ ) N-,-(CH ₃ CO) N-, or -O-, Y: -CH ₂ -,-(CH ₃ ) N-,-(CH ₃ CH ₂ ) N-,-(CH ₃ CO) N-, or -O-, Z: -CH ₂ -, or -O- (but, in X comprises N or O , Y is -CH ₂ -, when Y contains N at or O, X is -CH ₂ -). The compound of any one of claims 1 to 5 or a pharmacologically acceptable salt thereof, wherein X, Y and Z are one selected from the group consisting of: (1) X:-(C1-C6 alkyl) N-, Y: -CH _2- , Z: -O-; (2) X:-((C1-C6 alkyl) carbonyl) N-, Y: -CH _2- , Z: -O-; (3 ) X: -CH _2- , Y:-(C1-C6 alkyl) N-, Z: -O-; (4) X: -CH _2- , Y:-((C1-C6 alkyl) carbonyl) N-, Z: -O-; (5) X: -CH _2- , Y: -O-, Z: -CH _2- . The compound or pharmacologically acceptable salt thereof according to claim 6, wherein X, Y and Z are one selected from the group consisting of: (1) X:-(CH ₃ ) N-, Y: -CH _2- , Z: -O-; (2) X:-(CH ₃ CH ₂ ) N-, Y: -CH _2- , Z: -O-; (3) X:-(CH ₃ CO) N-, Y : -CH _2- , Z: -O-; (4) X: -CH _2- , Y:-(CH ₃ ) N-, Z: -O-; (5) X: -CH _2- , Y: -(CH ₃ CH ₂ ) N-, Z: -O-; (6) X: -CH _2- , Y :-( CH ₃ CO) N-, Z: -O-; (7) X: -CH _2- , Y: -O-, Z: -CH _2- . The compound or pharmacologically acceptable salt thereof according to claim 6, wherein X, Y and Z are one selected from the group consisting of: (1) X:-(CH ₃ ) N-, Y: -CH _2- , Z: -O-; (2) X: -CH _2- , Y:-(CH ₃ ) N-, Z: -O-; (3) X: -CH _2- , Y: -O-, Z : -CH _2- . The compound of claim 1 or a pharmacologically acceptable salt thereof is selected from the group consisting of a compound represented by the following structural formula: If the compound of claim 1 or a pharmacologically acceptable salt thereof is represented by the following structural formula: If the compound of claim 1 or a pharmacologically acceptable salt thereof is represented by the following structural formula: If the compound of claim 1 or a pharmacologically acceptable salt thereof is represented by the following structural formula: If the compound of claim 1 or a pharmacologically acceptable salt thereof is represented by the following structural formula: If the compound of claim 1 or a pharmacologically acceptable salt thereof is represented by the following structural formula: If the compound of claim 1 or a pharmacologically acceptable salt thereof is represented by the following structural formula: If the compound of claim 1 or a pharmacologically acceptable salt thereof is represented by the following structural formula:     A pharmaceutical composition containing the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient.         The pharmaceutical composition according to claim 17, which is used for preventing or treating obesity.         A use of a compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for preventing or treating obesity.         A compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof for use in the prevention or treatment of obesity.         A method for preventing or treating obesity by administering an effective amount of a compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof.         The pharmaceutical composition according to claim 17 for the prevention or treatment of type 2 diabetes.         A use of a compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for preventing or treating type 2 diabetes.         A compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof for use in the prevention or treatment of type 2 diabetes.         A method for preventing or treating type 2 diabetes by administering an effective amount of a compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof.